Fiber optic integrated-light diffusers for sensing applications

ABSTRACT

Embodiments include a fiber optic probe comprising an optical fiber, and a sensor component attached to the optical fiber, the sensor component including an asymmetric microlens array imprinted on a stimuli-responsive hydrogel. Embodiments further include a method of fabricating a fiber optic probe comprising depositing a stimuli-responsive hydrogel precursor solution on a substrate mold, the substrate mold including a concave asymmetric microlens array; contacting an end of an optical fiber with the stimuli-responsive hydrogel precursor solution deposited on the substrate mold; and exposing the end of the optical fiber and the stimuli-responsive hydrogel precursor solution to light to form a stimuli-responsive hydrogel sensor imprinted with a convex asymmetric microlens array and attached to the end of the optical fiber. Embodiments further include systems comprising the fiber optic probes.

BACKGROUND

It has been reported that certain fiber optic probes can be used forsensing applications. For example, fiber optic probes based onFabry-Perot interferometry, surface plasmon resonance, amplitudeabsorbance measurements, and organic dyes have been reported for sensingapplications. However, these fiber optic probes are limited in that theyrequire high-quality films, coherent light sources, high-costinstrumentation, bulky equipment, complicated output signal processing,and complex fabrication processes, among other things.

SUMMARY

According to one or more aspects, a fiber optic probe can include anoptical fiber, and a sensor component attached to the optical fiber, thesensor component including an asymmetric microlens array imprinted on astimuli-responsive hydrogel.

According to one or more further aspects, a method of fabricating afiber optic probe can include (a) depositing a light-curablestimuli-responsive hydrogel precursor solution on a substrate moldhaving a surface including an inverse asymmetric microlens array; (b)contacting an end portion of an optical fiber with the light-curablestimuli-responsive hydrogel precursor solution deposited on thesubstrate mold; and (c) exposing the end portion of the optical fiberand light-curable stimuli-responsive hydrogel precursor solution tolight to form a stimuli-responsive hydrogel sensor imprinted with anasymmetric microlens array and attached to the end portion of theoptical fiber.

According to one or more additional aspects, a system can include afiber optic probe including an optical fiber and a sensor componentattached to the optical fiber, the sensor component including anasymmetric microlens array imprinted on a stimuli-responsive hydrogel; alight source coupled to the fiber optic probe, wherein the light sourceis configured to transmit light through the optical sensor; and a lightsensor for detecting light transmitted through the asymmetric microlensarray or light reflected from the asymmetric microlens array.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a schematic diagram of a fiber optic probe in accordance withone or more embodiments of the invention.

FIG. 1B is a schematic diagram of an asymmetric microlens arrayimprinted on a stimuli-responsive hydrogel in accordance with one ormore embodiments of the invention.

FIG. 1C is a schematic diagram showing the side profile of a microlensarray taken along line 1-1 in accordance with one or more embodiments ofthe invention.

FIGS. 2A-2J are schematic diagrams showing the side profile of variousmicrolenses in accordance with one or more embodiments of the invention.

FIG. 3 is a flowchart of a method of fabricating a fiber optic probe inaccordance with one or more embodiments of the invention.

FIG. 4 is a flowchart of a method of fabricating a substrate mold from amaster light diffuser in accordance with one or more embodiments of theinvention.

FIG. 5 is a flowchart of a method of fabricating an optical fiber inaccordance with one or more embodiments of the invention.

FIG. 6 is a schematic diagram of a system configured to operate intransmission mode in accordance with one or more embodiments of theinvention.

FIG. 7 is a schematic diagram of a system configured to operate inreflection mode in accordance with one or more embodiments of theinvention.

FIGS. 8A-8C are schematic diagrams illustrating (A) the fabrication of ahydrogel sensor imprinted with an asymmetric microlens array andconstrained on a glass substrate, wherein a monomer solution waspipetted onto a master of the asymmetric microlens array and coveredwith a silanized glass slide before being exposed to UV-light forcuring; (B) the fabrication of a biocompatible optical fiber, wherein amonomer solution was injected into a tube mold and polymerized byUV-light, which was then extracted by applying water pressure; (C) thefabrication of a fiber optic probe in which an end of the optical fiberis functionalized by dropcasting a droplet of 20 μl of a monomersolution on an asymmetric microlens array replica (or, in someinstances, master) and a silanized optical fiber tip was contacted withthe droplet and cured for 60 min, in accordance with one or moreembodiments of the present invention.

FIGS. 9A-9E relate to the interrogation of an alcohol-responsivehydrogel sensor attached chemically to a glass slide, showing (A) aschematic diagram of the setup utilized to interrogate the sensors whichincluded a laser pointer, a sample holder, and a power meter; (B)-(D)graphical views of the spatial optical profile of the transmitteddiffused light beam from the alcohol-responsive hydrogel based sensorwhile the sensor was tested in ethanol, propan-2-ol, and DMSO,respectively; and (E) a graphical view showing the maximum transmittedpower (P_(t)) of the laser beam passing through the alcohol-responsivehydrogel based sensor submerged in various alcohol concentrations, inaccordance with one or more embodiments of the present invention.

FIGS. 10A-10I relate to the interrogation of a fiber optic probe foralcohol sensing in a transmission configuration and a reflectionconfiguration, showing (A) a schematic of the setup utilized toinvestigate the fiber optic probe's response in transmission mode, withthe setup including fiber probe coupled to a laser pointer at one endand the alcohol-responsive hydrogel sensor attached to the end of theoptical fiber was soaked in an alcohol solution container placed over aphotodetector or a smartphone; (B)-(C) microscopic images of a multimodesilica fiber; (D) photographs of a silica fiber with a hydrogel sensorattached to an end thereof guiding different monochromatic light beams;(E) graphical views showing the maximum optical transmitted power(P_(t)) from the fiber optic probe versus alcohol concentrations whilesaid probe was illuminated with a green laser (532 nm) and the outputsignals were recorded with an optical power meter; (F) a graphical viewshowing the illuminance of the fiber optic probe detected by asmartphone while the probe was submerged in various alcoholconcentrations recorded and illuminated by a white light source; (G) aschematic of the setup utilized to investigate the fiber optic probe inreflection mode, where the fiber optic probe was coupled with a whitelight source and a power meter using a 2×1 coupler and where the couplerincluded seven optical fibers, with one fiber illuminating the fiberoptic probe and the other six fibers guiding reflected light from theprobe to the power meter; (H) a graphical view showing reflected powerthrough the fiber optic probe versus alcohol concentrations; and (I) agraphical view showing the maximum transmitted power (P_(t)) of thefiber optic probe tested in ethanol (5% v/v) and DI water for 6 cyclesversus time, in accordance with one or more embodiments of the presentinvention.

FIGS. 11A-11K relates to interrogation of the pH-responsive hydrogelsensor attached chemically on a glass slide and the fiber optic probefor pH sensing in a transmission configuration and a reflectionconfiguration, showing (A) a graphical view of the spatial opticalprofiles of the transmitted diffused light passing through thepH-responsive hydrogel sensor while the pH-responsive hydrogel sensorwas submerged in various pH solutions and illuminated by a green laserbeam, 532 nm at 24° C.; (B) a graphical view showing the maximumtransmitted power for the beam passing through the pH-sensor submergedin various pH solutions; (C) a schematic diagram of the setup utilizedfor testing the pH-responsive hydrogel sensor in reflection mode, wherethe sensor was illuminated by a monochromatic beam (532 nm) and thereflected signal was picked up by an optical power meter; (D) agraphical view showing the maximum optical reflected power from thepH-responsive hydrogel sensor exposed to various pH solutions andilluminated by a green laser beam; (E) a schematic diagram of the setuputilized for testing the fiber optic probe in transmission mode; (F) agraphical view showing the maximum transmitted power of the fiber proberecorded when the functionalized probe tip was submerged in various pHsolutions; (G) a graphical view showing the maximum illuminance emittedfrom the fiber optic probe recorded by a smartphone when the probe wassubmerged in different pH solutions; (H) a graphical view showing thereflected power in the fiber optic probe recorded by the optical powermeter when the fiber optic probe was soaked in various pH solutions; (I)a graphical view showing kinetic swelling of the pH-responsive hydrogelsensor when said hydrogel sensor was soaked in a pH 6.0 solution andP_(t) was recorded; (J) a graphical view showing the maximum transmittedpower of the fiber tested in two different pH solutions for 3 cyclesversus time; (k) a graphical view showing the reflected optical power inthe biocompatible fiber probe when it was submerged in various pHsolutions, in accordance with one or more embodiments of the presentinvention.

FIGS. 12A-12D are schematic diagrams showing (A) a method of preparing aglass-constrained glucose-responsive hydrogel sensor stamped with anasymmetric microlens array; (B)-(C) the functionalization process of thesilica and hydrogel optical fibers; and (D) the fabrication process forthe biocompatible hydrogel fiber, in accordance with one or moreembodiments of the present invention.

FIGS. 13A-13F relate to the quantification of glucose concentration by aglucose-responsive hydrogel sensor, showing (A) a schematic diagram ofthe setup utilized for recording glucose concentrations in transmissionmode; (B) a graphical view showing the profile of the opticaltransmitted power passing through the sensor against glucoseconcentrations when the sensor was illuminated by a green laser (532nm); (C) a graphical view showing the P_(t) of the sensor at variousglucose concentrations (0-50 mM), with the inset showing the glucoserange of 0-20 mM; (D) a schematic diagram of the setup utilized forinterrogating the glucose sensor in the reflection mode; (E) a graphicalview showing the maximum transmitted illuminance (L_(t)) of the sensorversus glucose concentrations while the sensor was illuminated by thebroadband white light beam, and the illuminance was recorded by anambient light sensor of a smartphone; and (F) a graphical view of theP_(r) of the hydrogel sensor for various glucose concentrations capturedin reflection mode, with the inset showing the glucose concentrationsrange of 0-20 mM, in accordance with one or more embodiments of thepresent invention.

FIGS. 14A-14I relate to detection of glucose using a glucose-responsivehydrogel sensor attached to a silica optical fiber in transmission mode,showing (A) a schematic diagram of the setup utilized to test thefunctionalized fiber in transmission mode; (B)-(C) optical microscopyimages of the silica multimode fiber; (D) photographs of the silicafiber optic probe coupled to blue, green, and red lasers; (E) agraphical view showing the maximum optical transmitted power (P_(t)) ofthe functionalized fiber submerged in various glucose concentrationsover time; (F) a graphical view showing the P_(t) of the fiber againstglucose concentrations (0-50 mM), while the fiber optic probe wascoupled with a green laser and the readout was recorded by a powermeter, with the inset showing measurements for the glucose range of 5-20m; (G) a graphical view showing the L_(t) of the fiber optic probeversus glucose concentrations where the fiber optic probe was coupled toa green laser pointer and the readouts were captured by an ambient lightsensor of a smartphone, with the inset showing the glucose concentrationrange of 5-20 mM; (H) a graphical view showing the L_(t) of the fiberoptic probe versus glucose concentrations while the fiber optic probewas coupled with a broadband white light source and the output signalswere captured by an ambient light sensor of a smartphone, with the insetshowing the glucose concentration range of 5-20 mM; and (I) a graphicalview showing the P_(t) of the fiber optic probe versus glucoseconcentrations where the fiber optic probe was coupled with a broadbandwhite light source and the output signals were recorded by an opticalpower meter, with the inset showing the glucose concentration range of5-20 mM, in accordance with one or more embodiments of the presentinvention.

FIGS. 15A-15G relate to the silica fiber optic probe used for glucosesensing in reflection mode, showing (A) a schematic diagram of the setuputilized for interrogating the fiber optic probe in the reflectionconfiguration; (B) a graphical view showing the optical reflected powerversus the glucose concentrations while the fiber optic probe wascoupled with a white light source and the output signal was captured byan optical power meter; (C) a graphical view showing the maximumtransmitted power of the fiber optic probe over time at 10 mM glucoseconcentration; (D) a graphical view showing the fiber optic probe'soutput signal versus time at a glucose concentration of 10 mM for fourcycles as the green laser laser pointer coupled with the fiber opticprobe and the readings were recorded in transmission mode, the fiberoptic probe was reset in acetate buffer (pH 4.6), and the transmittedpower baseline was 611±1 μW and increased to 623±1 μW; (E) a graphicalview showing the lactate and glucose concentrations versus the P_(t) athuman body temperature, 37° C., the test was carried out in transmissionmode; (F) a graphical view showing the solution's pH against the fiberoptic probe's output signal recorded in the transmission mode; (G) agraphical view showing solution temperature versus the fiber opticprobe's output signals, the test was carried out in transmission mode,in accordance with one or more embodiments of the present invention.

FIGS. 16A-16D relate to stimuli-responsive hydrogel sensors, showing (A)photographs of a fiber optic probe and a PEGDA hydrogel cubes of variousprecursor concentrations; (B) a graphical view showing the attenuationof green and red laser beams (532 and 650 nm) versus the precursorconcentration (5-90 vol %); (C) a graphical view showing the attenuationof the white light by the hydrogels of 1 cm cube side versus theprecursor concentrations; (D) a graphical view showing testing relatingto the biocompatible functionalized fiber for glucose detection in thereflection configuration, where the optical reflected power values wererecorded by the power meter versus glucose concentrations, in accordancewith one or more embodiments of the present invention.

FIGS. 17A-17B show (A) an optical microscopic image of light diffusingmicrostructures (an asymmetric microlens array) replicated on a hydrogelsurface and (B) a graphical view showing a distribution of the lightdiffusing microstructures, in accordance with one or more embodiments ofthe present invention.

FIG. 18 is a schematic diagram showing glucose-boron complexation in ahydrogel matrix inducing a positive volumetric shift, in accordance withone or more embodiments of the present invention.

DETAILED DESCRIPTION

The present invention relates to fiber optic-integrated light diffusersfor sensing applications. More specifically, the present inventionrelates to fiber optic probes that include light diffusingmicrostructures imprinted on a stimuli-responsive polymeric materialthat is attached to an end portion of an optical fiber and can be usedfor sensing parameters. The fiber optic probes disclosed herein cansense a wide variety of parameters with high sensitivity and rapidresponse times, while also overcoming many of the challenges andshortcomings of conventional fiber optic probes in terms of fabrication,practicality, portability, and readout methodology. For example, inaddition to being reusable, offering electromagnetic immunity, remoteand implantable sensing capabilities, miniaturization, and low volumesamples, the fiber optic probes of the present invention do not requirehigh quality films, coherent light sources, costly instrumentation,bulky equipment, complex fabrication techniques, or output signalprocessing. For example, some embodiments disclose a method offabricating fiber optic probes in which the sensor component issynthesized, imprinted with light diffusing microstructures, andattached to an optical fiber to form the fiber optic probe in a singlesimple and easy step. The fiber optic probes thus avoid the challengingsteps involved in, for example, fabricating high quality films, formingprecisely shaped droplets as sensors, and immobilizing a hydrogel on athin metal layer.

As described above, the fiber optic probes of the present inventiongenerally comprise a sensor component attached to an end of an opticalfiber. The sensor component can include a stimuli-responsive polymericmaterial imprinted with light diffusing microstructures that form anasymmetric microlens array. While not wishing to be bound to a theory,it is believed that the light diffusing microstructures can modulate theincident angle of reflected rays in the optical fiber. For example, inthe presence or absence of at least one stimulus, a polymeric materialsuch as a hydrogel can undergo a positive or negative volumetric shiftthat alters the refractive index and the dimensions of the lightdiffusing microstructures. A positive volumetric shift can, for example,decrease the scattering angle of reflected rays in the core of theoptical fiber such that more rays satisfy the guidance condition andremain confined in the fiber core. As a result, the optical power fromthe fiber optic probe can undergo a change (e.g., an increase or adecrease) in response to the stimulus and this change in optical powercan be correlated to the parameter(s) being sensed, such as a pH level,analyte concentration, etc.

The versatility of the materials that can be used to form the fiberoptic probes and the wide range of parameters capable of being sensed bythese materials provides a high degree of flexibility and tunability,and thus broadens the scope of sensing applications in which the fiberoptic probes can be used. For example, embodiments describe fiber opticprobes that can be used in remote sensing and implantable biosensingapplications. Accordingly, the term sensing is used broadly herein andrefers to any type of sensing known in the art. For example, the fiberoptic probes can be used for sensing at least one parameter, detectingat least one parameter, measuring at least one parameter, monitoring atleast one parameter, and so on. In addition, the parameters capable ofbeing sensed are not particularly limited, given that sensor componentssuch as stimuli-responsive hydrogels can be customized (e.g., via theselection and combination of monomer and/or crosslinker, relativeamounts of monomer and/or crosslinker, etc.) to sense a particularparameter (e.g., pH, etc.) or a particular range of a parameter (e.g.,pH levels between 5-7). Parameters capable of being sensed by the fiberoptic probes disclosed herein include, for example and withoutlimitation, analytes, analyte concentrations, temperatures, pH levels,ionic strength, wavelengths of light, ion concentrations, electricfields, magnetic fields, solvents, pressures, and the like. For example,the fiber optic probes can be used in remote or implantable applicationsfor continuous or intermittent real-time quantitative sensing,monitoring, detecting, and/or measuring of glucose, lactates, proteins,DNA, alcohols, metabolites, biomarkers, pH (e.g., gastric pH), oxygen,compounds containing oxygen such as metal oxides and/or metal hydroxides(e.g., rusting), carbon dioxide, in various aqueous solutions such ashuman blood and/or plasma, among others.

Referring now to FIG. 1A, an isometric view of a fiber optic probe 100is shown, according to one or more embodiments of the invention. Thefiber optic probe 100 comprises an optical fiber 110 and a sensorcomponent 120. The optical fiber 110 has a proximal end 112 and a distalend 114. The sensor component 120 is attached to the distal end 114 ofthe optical fiber 110 and includes a stimuli-responsive polymericmaterial 122. Light diffusing microstructures forming an asymmetricmicrolens array 124 can be imprinted on the stimuli-responsive polymericmaterial 122 to obtain the sensor component 120.

The optical fiber 110 and sensor component 120 can be attached viavarious types of associative interactions. Examples of associativeinteractions include, without limitation, chemical interactions,physical interactions, and combinations thereof. In some embodiments,the sensor component 120 is chemically attached to the optical fiber110. In some embodiments, the sensor component 120 is covalently bondedto the optical fiber 110. In some embodiments, the sensor component 120is attached to the optical fiber 110 via hydrogen bonding. In someembodiments, the sensor component 120 is attached to the optical fiber110 via ionic interactions. In some embodiments, the sensor component120 is attached to the optical fiber 110 via electrostatic dipole-dipoleinteractions. In some embodiments, the sensor component 120 is attachedto the optical fiber 110 via van der Waal's forces. In some embodiments,the sensor component 120 is attached to the optical fiber 110 via one ormore of covalent bonding, hydrogen bonding, ionic interactions,electrostatic dipole-dipole interactions, and van der Waal's forces,among other covalent and noncovalent interactions.

The optical fiber 110 is not particularly limited. The optical fiber 110can include a core and the core can optionally be surrounded by one ormore layers, such as cladding, polymer coatings, protective outerjackets, and the like, or the optical fiber 110 can comprise or consistof a core, wherein the core can comprise or consist of a polymericmaterial. Suitable optical fibers 110 include single-mode optical fibersand multi-mode optical fibers. For example, in some embodiments, theoptical fiber 110 includes a multi-mode silica fiber. Other commerciallyavailable optical fibers can also be used as the optical fiber 110. Inaddition, the incompatibility of optical fibers, such as those which arecommercially available, with biological tissues can limit their use inmedical diagnostics due to the immune reactions in vivo. Accordingly, insome embodiments, the optical fiber 110 comprises or consists ofbiocompatible polymeric materials, such as hydrogels, formed inaccordance with the methods disclosed herein. Exemplary biocompatiblepolymeric materials include light-curable and in particular UV-curablepolymers and hydrogels, such as certain stimuli-responsive hydrogels.For example, in some embodiments, the optical fiber 110 comprises orconsists of polyethylene glycol diacrylate. In some embodiments, theoptical fiber 110 comprises or consists of polyethylene glycoldiacrylate (PEGDA) and 2-hydroxy-2-methylpropiophenone (2-HMP). In someembodiments, the optical fiber 110 comprises a biocompatible material,such as PEDGA and/or 2-HMP, and a low refractive index material, such ascalcium alginate, surrounding the biocompatible core as biocompatiblecladding.

Additional examples of polymeric materials that can be included in theoptical fibers 110 or used to form the optical fibers 110 and/orbiocompatible cladding include, without limitation, natural or syntheticmonomers, polymers, and copolymers, as well as biocompatible monomers,polymers, and copolymers. For example, in some embodiments, the opticalfibers 110 and biocompatible cladding can include one or more of thefollowing: polystyrene, neoprene, polyetheretherketone (PEEK), carbonreinforced PEEK, polyphenylene, polyetherketoneketone (PEKK),polyaryletherketone (PAEK), polyphenylsulphone, polysulphone,polyurethane, polyethylene, low-density polyethylene (LDPE), linearlow-density polyethylene (LLDPE), high-density polyethylene (HDPE),polypropylene, polyetherketoneetherketoneketone (PEKEKK), nylon,fluoropolymers such as polvtetrafluoroethylene (PTFE or TEFLON®),TEFLON® TFE (tetrafluoroethylene), polyethylene terephthalate (PET orPETE), TEFLON® FEP (fluorinated ethylene propylene), TEFLON® PFA(perfluoroalkoxy alkane), and/or polymethylpentene (PMP), styrene maleicanhydride, styrene maleic acid (SMA), polyurethane, silicone, polymethylmethacrylate, polyacrylonitrile, poly (carbonate-urethane),poly(amylacetate), nitrocellulose, cellulose acetate, urethane,urethane/carbonate, polylactic acid, polyacrylamide (PAAM),poly(N-isopropylacrylamide)(PNIPAM), poly(vinylmethylether),poly(ethylene oxide), poly(ethyl (hydroxyethyl) cellulose), poly(2-ethyloxazoline), polylactide (PLA), polyglycolide (PGA),poly(lactide-co-glycolide) PLGA, poly(ε-caprolactone), polydiaoxanone,polyanhydride, trimethylene carbonate, poly(hydroxybutyrate), poly(ethylglutamate), poly(DTH-iminocarbonate), poly(bisphenol A iminocarbonate),poly(orthoester) (POE), polycyanoacrylate (PCA), polyphosphazene,polyethyleneoxide (PEO), polyethylene glycol (PEG) or any of itsderivatives, polyacrylacid (PAA), polyacrylonitrile (PAN),polyvinylacrylate (PVA), polyvinylpyrrolidone (PVP), polyglycolic lacticacid (PGLA), poly(hydroxypropylmethacrylamide) (PHPMAm), polyvinylalcohol (PVOH), PEG diacrylate (PEGDA), poly(hydroxyethyl methacrylate)(PHEMA), N-isopropylacrylamide (NIPA), polyoxazoline (POx), poly(vinylalcohol)-poly(acrylic acid) (PVOH-PAA), collagen, silk, fibrin, gelatin,hyaluron, cellulose, chitin, dextran, casein, albumin, ovalbumin,heparin sulfate, starch, agar, heparin, alginate, fibronectin, fibrin,keratin, pectin, elastin, ethylene vinyl acetate, ethylene vinyl alcohol(EVOH), polyethylene oxide, PLLA (poly(L-lactide) or poly(L-lacticacid)), poly(D,L-lactic acid), poly(D,L-lactide), polydimethylsiloxane(PDMS), poly(isopropyl acrylate) (PIPA), polyethylene vinyl acetate(PEVA), PEG styrene, polytetrafluoroethylene RFE such as TEFLON® RFE orKRYTOX® RFE, fluorinated polyethylene (FLPE or NALGENE®), methylpalmitate, poly(N-isopropylacrylamide) (NIPA), polycarbonate,polyethersulfone, polycaprolactone, polymethyl methacrylate,polyisobutylene, nitrocellulose, medical grade silicone, celluloseacetate, cellulose acetate butyrate, polyacrylonitrile,poly(lactide-co-caprolactone) (PLCL), and/or chitosan.

The dimensions of the optical fibers 110 can vary widely and thus arenot particularly limited. For example, the diameter of the optical fiber110 can vary from a few micrometers up to sizes on the scale ofmillimeters, with the lengths capable of being similar in scale or evenlarger. In some embodiments, for example, the diameter of the opticalfiber 110 is about 500 microns. In some embodiments, the diameter of theoptical fiber 110 is about 950 microns and about 5 cm in light. In someembodiments, the diameter of the optical fiber 110 is about 1 mm. Theseshall not be limiting as other dimensions can be utilized herein withoutdeparting from the scope of the present invention.

As described above, the sensor component 120 includes an array of lightdiffusing microstructures. In some embodiments, the array 124 of lightdiffusing microstructures includes a plurality of microlenses. Forexample, in some embodiments, the light diffusing microstructures and/orthe plurality of microlenses form an asymmetric microlens array 124. Atleast one advantage of the asymmetric microlens array 124 is that it canincrease the active area of the sensor component 120 and enhance thediffusion rate of the analyte into the a polymeric and/or hydrogelmatrix, thereby shortening response times and/or improving sensitivity,among other things. In some embodiments, an asymmetric microlens array124 can refer to a microlens array including a plurality of microlensesand having at least one aspect which is nonuniform, or asymmetric. Forexample, the term includes microlens arrays having at least twomicrolenses which are different from each other in at least one aspect.The aspect(s) in which the microlens array and/or microlenses arenonuniform (e.g., different, asymmetric, etc.) is not particularlylimited and can include, for example and without limitation, thedistribution and/or arrangement of microlenses, the spacing betweenmicrolenses, as well as the size, shape, and/or surface topology of themicrolenses.

For example, in some embodiments, the asymmetric microlens array 124includes microlenses which are nonuniformly spaced apart. In someembodiments, the asymmetric microlens array 124 includes microlenseswhich are arranged in a nonordered distribution. In some embodiments,the asymmetric microlens array 124 includes microlenses which arearranged in a nonperiod configuration. In some embodiments, theasymmetric microlens array 124 includes microlenses, or at least twomicrolenses, which differ in at least one base dimension (e.g., length,width, diameter, etc.). In some embodiments, the asymmetric microlensarray 124 includes microlenses, or at least two microlenses, whichdiffer in base geometry (e.g., shape). In some embodiments, theasymmetric microlens array 124 includes microlenses, or at least twomicrolenses, which differ in height. In some embodiments, the asymmetricmicrolens array 124 includes microlenses, or at least two microlenses,which have different side profiles (e.g., cross-sectional shape). Insome embodiments, the asymmetric microlens array 124 includesmicrolenses, or at least two microlenses, which differ in surfacetopology.

In some embodiments, the asymmetric microlens arrays 124 can includemicrolenses having other features. In some embodiments, the asymmetricmicrolens array 124 includes one or more microlenses, wherein each ofthe one or more microlenses can independently have an aspherical orspherical surface. For example, in some embodiments, the asymmetricmicrolens array 124 includes at least one microlense having anaspherical surface. In some embodiments, the asymmetric microlens array124 includes at least one microlense having a spherical surface.

In some embodiments, each microlense and/or its surface can be concave,convex, plano-concave, plano-convex, convex-concave, and/orconcave-convex, where convex means outwardly facing, for example, awayfrom the optical fiber. In some embodiments, the asymmetric microlensarray 124 includes at least one microlense having a convex asphericalsurface. In some embodiments, the asymmetric microlens array 124includes at least one microlense having a plano-convex asphericalsurface. In some embodiments, the asymmetric microlens array 124includes at least one microlense having a convex-concave asphericalsurface. In some embodiments, the asymmetric microlens array 124includes at least one microlense having a convex-concave asphericalsurface. In some embodiments, the asymmetric microlens array 124includes at least one microlense having a convex spherical surface. Insome embodiments, the asymmetric microlens array 124 includes at leastone microlense having a plano-convex spherical surface. In someembodiments the asymmetric microlens array 124 includes at least onemicrolense having a convex-concave spherical surface. In someembodiments, the asymmetric microlens array 124 includes at least onemicrolense having a convex-concave spherical surface.

In some embodiments, the asymmetric microlens array 124 includes atleast one microlense having a concave aspherical surface. In someembodiments, the asymmetric microlens array 124 includes at least onemicrolense having a plano-concave aspherical surface. In someembodiments, the asymmetric microlens array 124 includes at least onemicrolense having a concave-convex aspherical surface. In someembodiments, the asymmetric microlens array 124 includes at least onemicrolense having a concave-convex aspherical surface. In someembodiments, the asymmetric microlens array 124 includes at least onemicrolense having a concave spherical surface. In some embodiments, theasymmetric microlens array 124 includes at least one microlense having aplano-concave spherical surface. In some embodiments the asymmetricmicrolens array 124 includes at least one microlense having aconcave-convex spherical surface. In some embodiments, the asymmetricmicrolens array 124 includes at least one microlense having aconcave-convex spherical surface.

In some embodiments, the asymmetric microlens array 124 includes one ormore conical-shaped microlenses. In some embodiments, the asymmetricmicrolens array 124 includes one or more hemispherical-shapedmicrolenses. In some embodiments, the asymmetric microlens array 124includes one or more aspherical-shaped microlenses. In some embodiments,the asymmetric microlens array 124 includes one or morecylindrical-shaped microlenses. In some embodiments, the asymmetricmicrolens array 124 includes hyperbolic-shaped microlenses. In someembodiments, the asymmetric microlens array 124 includes one or more ofmicro-spheres, micro-pikes, micro-pyramids, micro-grooves, micro-cones,micro-peaks, micro-blocks, among others. In some embodiments, theasymmetric microlens array 124 includes any one or more of the foregoingand other features disclosed elsewhere herein.

The light diffusing microstructures and, in particular, the asymmetricmicrolens arrays 124 can be imprinted on a stimuli-responsive polymericmaterial 122 to form the sensor component 120. Exemplarystimuli-responsive polymeric materials 122 include light-curablestimuli-responsive hydrogels which can be imprinted with an asymmetricmicrolens array 124 to form hydrogel sensors 120. Other polymericmaterials which can undergo a change in at least one property inresponse to at least one stimulus can also be utilized herein as thestimuli-responsive polymeric material 122. Suitable polymeric materialsinclude, for example and without limitation, natural or syntheticpolymers (e.g., hydrogels, homopolymers, copolymers, terpolymers,polymer blends, etc.), oligomers, monomers, and the like, such as thosedescribed above in relation to the optical fibers. The change caninclude physical changes, chemical changes, or both physical changes andchemical changes. For example, the changes can include a change fromhydrophilic to hydrophobic (and vice versa), changes in color and/ortransparency, changes in conductivity, changes in permeability, changesin shape, as well as reversible conformational changes and/orphysico-chemical changes, such as folding/unfolding transitions,reversible precipitation behavior, or other conformational changes. Theat least one stimulus can include at least one of temperature, pH,pressure, wavelength of light, ionic strength, ion concentration,analyte concentration, electric field, magnetic field, solvent, and thelike. Examples of stimuli-responsive polymeric materials include,without limitation, temperature-responsive polymers, pH-responsivepolymers, light-responsive polymers, ion-responsive polymers,analyte-responsive polymers (e.g., for sensing oxygen, carbon dioxide,glucose, etc.), and the like. Additional examples of polymers include,without limitation, block copolymers and graft copolymers having one ormore stimuli-responsive polymer components. For example, astimuli-responsive block copolymer can include a temperature-sensitivepolymer block. A stimuli-responsive graft copolymer can include apH-responsive polymer backbone or pendant temperature-sensitive polymercomponents. the stimuli-responsive polymeric materials can in additionor in the alternative include any of the polymeric materials disclosedabove in the discussion regarding the optical fibers.

Referring now to FIG. 1B, an isometric view of the sensor component 120is provided to illustrate the asymmetric microlens array 124 in moredetail, according to one or more embodiments of the invention. In theillustrated embodiment, the asymmetric microlens array 124 is imprintedon a stimuli-responsive hydrogel 122 and includes a plurality of convexaspherical microlenses, such as convex aspherical microlenses 126A,126B, 126C. The plurality of convex aspherical microlenses forming theasymmetric microlens array 124 are arranged in a nonordered, nonperiodicconfiguration, with nonuniform spacing between adjacent microlenses.Further, the plurality of convex aspherical microlenses have nonuniformbase dimensions, nonuniform base geometries, and nonuniform heights. Inaddition, the plurality of convex microlenses have nonuniform surfacetopologies and side profiles. FIG. 1C is a side profile view of aportion of the asymmetric microlens array 120 taken long the line 1-1,illustrating various nonuniform shapes, side profiles, heights, basedimensions, spacing between microlenses, and surface topologies ofmicrolenses, according to one or more embodiments of the invention.While the microlenses shown in FIG. 1C include plano-convex microlenses,other configurations are possible and thus shall not be limiting.

Referring now to FIGS. 2A-2J, side profile views of generallyplano-convex aspherical microlenses are shown to illustrate thevariation among the microlenses in terms of shapes and surfacetopologies, according to one or more embodiments of the invention. Oneor more of the aspherical microlenses shown in FIGS. 2A-2J can beimprinted on a stimuli-responsive polymeric material. The side profileviews presented in FIGS. 2A-2J are nonlimiting. Microlenses can haveside profiles other than those presented in FIGS. 2A-2J. The sideprofile views shown in those figures were presented to illustrate thevariations and diversity of shapes and surface topologies of microlenseswhich can be utilized herein.

Referring now to FIG. 3, a flowchart of a method of fabricating a fiberoptic probe is shown, according to one or more embodiments of theinvention. As shown in FIG. 3, the method 300 of fabricating a fiberoptic probe can comprise one or more of the following steps: depositing302 a polymeric precursor solution on a substrate mold; contacting 304an end portion of an optical fiber with the deposited polymericprecursor solution; and exposing 306 at least the end portion of theoptical fiber and the deposited polymeric precursor solution to light.At least one advantage of the present method, among others, is that thesensor component can be synthesized (e.g., a hydrogel can be synthesizedand/or crosslinked), imprinted with light diffusing microstructures(e.g., an asymmetric microlens array), and attached to the end portionof the optical fiber in a single step, such as step 306. Otheradvantages are or will become apparent from the discussion below andelsewhere herein.

In step 302, a polymeric precursor solution is deposited on a surface ofa substrate mold. The surface of the substrate mold can be stamped orimprinted with the inverse structure of the desired asymmetric microlensarray. For example, in embodiments in which the stimuli-responsivepolymeric material is to be imprinted with an asymmetric microlens arraythat includes a plurality of convex microlenses, the surface of thesubstrate mold will include a plurality of concave microlenses. Theinverse structure is used so that the resulting stimuli-responsivepolymeric material has the desired topology once it is peeled orreleased from the substrate mold. Conversely, the structure can beimprinted with a plurality of convex microlenses if thestimuli-responsive polymeric material is to be imprinted with anasymmetric microlens array that includes a plurality of convexmicrolenses. Accordingly, in some embodiments, the substrate mold has asurface including an inverse asymmetric microlens array.

Since the polymeric precursor solution, once polymerized, will form thestimuli-responsive polymeric material of the sensor component, thevolume or amount of the polymeric precursor solution to be deposited onthe substrate surface can depend on the size (e.g., the diameter) of theoptical fiber. For example, the volume of polymeric precursor solutionto be deposited on the surface of the substrate mold should besufficient to form a stimuli-responsive polymeric material that at leastpartially covers, or preferably, substantially or completely covers, theend or end portion of the optical fiber. Usually, an appropriate volumeof the polymeric precursor to be deposited is one that is sufficient tocover the portion of substrate mold that forms the asymmetric microlensarray. Since the such volumes are usually not relatively large volumes,the depositing can be performed by pipetting or drop-casting thepolymeric precursor solution onto the substrate surface, although othersimilar techniques, like coating, can be used. In addition, the volumeor amount of the polymeric precursor solution to be deposited can beadjusted to achieve a desired thickness of the stimuli-responsivepolymeric material following polymerization. As an example, in someembodiments, about 20 μL of the polymeric precursor solution isdeposited on the surface of the substrate mold.

As discussed above, the polymeric precursor solution includes precursorsthat can be polymerized, crosslinked, and/or cured to form thestimuli-responsive polymeric material. While any of the polymericmaterials disclosed herein and/or its precursors can be used, in someembodiments, the polymeric precursor solution includes precursors forlight-curable stimuli-responsive hydrogels, preferably UV-curablestimuli-responsive hydrogels. For example, the polymeric precursorsolution can include a light-curable stimuli-responsive hydrogelprecursor solution that includes one or more of the following: at leastone monomer, at least one photoinitiator, at least one crosslinkingagent, and at least one functionalizing agent. Additional examples ofcomponents that can be included in the precursor solution include,without limitation, oligomers, macromers, prepolymers, coinitiators,stabilizers, and plasticizers, among others. In some embodiments, theseprecursors can be exposed to ultraviolet light to synthesize ultravioletlight-curable (or UV-curable) stimuli-responsive hydrogels. In otherembodiments, precursors which are curable or crosslinked by othermeans—such as X-rays, microwaves, γ-radiation, thermal treatments, andthe like—can be utilized herein without departing from the scope of thepresent invention. In addition, other additives, such as pH adjustingagents, solvents, and wetting agents, can optionally be further includedin the polymeric precursor solution.

In some embodiments, the polymeric precursor solution is a hydrogelprecursor solution that can be implemented herein to form UV-curablestimuli-responsive hydrogels. In some embodiments, the UV-curablestimuli-responsive hydrogel includes a glucose-responsive hydrogel thatcan be used for glucose sensing. For example, in some embodiments, thehydrogel precursor solution includes acrylamide;N,N′-methylenebisacrylamide; 3-(acrylamido)-phenylboronic acid (3-APBA);and 2,2-dimethoxy-2-2phenylacetophenone (DMPA). In some embodiments, theUV-curable stimuli-responsive hydrogel includes an alcohol-responsivehydrogel that can be used for alcohol sensing. For example, in someembodiments, the hydrogel precursor solution includes2-hydroxyethylmethacrylate (HEMA); ethylene glycol dimethacrylate(EGDMA); and 2,2-dimethoxy-2-phenylacetophenone (DMPA). In someembodiments, the UV-curable stimuli-responsive hydrogel includes analcohol-responsive hydrogel that can be used for pH sensing. Forexample, in some embodiments, the hydrogel precursor solution includes2-hydroxyethylmethacrylate (HEMA); ethylene glycol dimethacrylate(EGDMA); acrylic acid (AA); and 2,2-dimethoxy-2-phenylacetophenone(DMPA). In some embodiments, the hydrogel precursor solution furtherincludes 2-(dimethylamino) ethyl methacrylate.

Other hydrogel precursor solutions can be used herein without departingfrom the scope of the present invention. For example, in someembodiments, the hydrogel precursor solution includes monomers and/orprepolymers of polyvinyl alcohol, polyvinyl pyrrolidone, a polyvinylpyrrolidone/vinyl acetate copolymer, a vinyl ether/anhydric maleic acidcopolymer, an isobutylene/anhydric maleic acid copolymer, amethoxyethylene/anhydric maleic acid copolymer, a methacrylic acid/butylacrylate copolymer, alginate, hydroxyethyl methacrylate, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrans,polysaccharides, a carboxyvinyl copolymer, polyethylene oxide,polyethylene glycol, polyacrylamide, polyhydroxyethyl methacrylate,polydioxolane, polyacrylic acid, sodium polyacrylate, polyvinylacrylate, polyacryl acetate, polyacrylamide, poly-N-vinyl pyrrolidinone,agarose, and polyvinyl chloride.

In some embodiments, the hydrogel precursor solution includes one ormore of the following, optionally as photoinitiators (e.g., ultravioletinitiators): phenylacetophenone, 2,2-dimethoxy-2-phenylacetophenone(DMPA), hydroxy dimethyl acetophenone, 4,4′-bis(dimethylamino)benzyl,methylbenzoylformate, diphenyl (2,4,6-trimethylbenzoyl)-phosphine oxide,phenyl bis(2,4,6-trimethyl benzoyl), oxy-phenyl-aceticacid-2-[2-oxo-2-phenyl-acetoxy-ethoxy]-ethyl ester, oxy-phenyl-aceticacid-2-[2-hydroxy-ethoxy]-ethyl ester, 4-cyclopentadiene-1-yl)bis[2,6-difluoro-3-(1-H-pyrrole-1-yl)phenyl]titanium,2-acetylnaphthalene, 2-naphthalaldehyde, iodonium salt, dicyclic acidderivatives, 9.10-anthraquinone, anthracene, pyrene, aminopyrene,perylene, phenanthrene, phenanthrenequinone, 9-fluorenone,dibenzosuberone, curcumin, xanthone, thiomichler's ketone,2,5-bis(4-diethylaminobenzyllidene)cyclopentanone,2-(4-dimethylamino-benzyllidene))-indan-1-one,α-(4-dimethylaminobenzyllidene))ketone such as3-(4-dimethylamino-phenyl)-1-indan-5-yl-propenone,3-phenylthiophthalimide, N-methyl-3,5-di(ethylthio)-phthalimide,N-methyl-3,5-di(ethylthio)-phthalimide, phenothiazine,methylphenothiazine, N-phenylglycine, amines such as triethanolamine andN-methyldiethanolamine, ethyl-p-dimethylaminobenzoate,2-(dimethylamino)ethylbenzoate, 2-ethylhexyl-p-dimethylaminobenzoate,octyl-para-N,N-dimethylaminobenzoate,N-(2-hydroxyethyl)-N-methyl-para-toluidine, butoxyethyl4-dimethylaminobenzoate, 4-dimethyl aminoacetophenone, triethanolamine,methyl di ethanol amine, dimethylaminoethanol, 2-(dimethylamino)ethylbenzoate, poly(propylene glycol)-4-(dimethylamino)benzoate, michler'sketone, 1-hydroxy-cyclohexyl-phenyl-ketone,2-hydroxy-2-methyl-1-phenyl-1-propanone,2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone,2-benzyl-2-(dimethylamino)-1-[4-(4-morpholinyl)phenyl]-1-butanone, and2-methyl-1-[4-(methylthio)phenyl]-2-(4-morpholinyl)-1-propanone.

In some embodiments, the hydrogel precursor solution includes one ormore of the following, optionally as photoinitiators (e.g., ultravioletinitiators): benzophenone, 4-phenyl benzophenone, 4-methoxybenzophenone, 4,4′-dimethyl benzophenone, 4,4′-dichlorobenzophenone,4,4′-bis(dimethylamino)-benzophenone,4,4′-bis(diethylamino)benzophenone,4,4′-bis(methylethylamino)benzophenone,4,4′-bis(p-isopropylphenoxy)benzophenone, 3,3′-dimethyl-4-methoxybenzophenone, methyl-2-benzoylbenzoate,4-(2-hydroxyethylthio)-benzophenone, 4-(4-tolylthio)benzophenone,1-[4-(4-benzoyl-phenylsulfanyl)-phenyl]-2-methyl-2(toluene-4-sulfonyl)-propane-1-one,4-benzoyl-N,N,N-trimethylbenzenemethanaminium chloride,2-hydroxy-3-(4-benzoyl-phenoxy)-N,N,N-trimethyl-1-propaneaminiumchloride monohydrate,4-(13-acryloyl-1,4,7,10,13-pentaoxatridecyl)-benzophenone, and4-benzoyl-N,N-dimethyl-N-[2-(1-oxo-2-prophenyl)oxy]ethyl-benzenemethanaminiumchloride.

In some embodiments, the hydrogel precursor solution includes one ormore of the following, optionally as crosslinking agents: ethyleneglycol dimethacrylate (EGDMA), benzyl methacrylate, lauryl methacrylate,isodecyl methacrylate, phenoxy methacrylate, 2-hydroxyethylmethacrylate, tetrahydro furfuryl methacrylate, cetyl(C16) methacrylate,stearyl methacrylate, methoxyPEG500 methacrylate, methoxyPEG600methacrylate, methoxyPEG1000 methacrylate, 1,6-hexandiol dimethacrylate,butadiene dimethacrylate, neopentylglycol dimethacrylate,ethyleneglycoldimethacrylate, diethyleneglycol dimethacrylate,triethyleneglycol dimethacrylate, tetraethyleneglycol dimethacrylate,bisphenol A(EO)4 dimethacrylate, bisphenol A(EO)3 dimethacrylate,bisphenol A(EO)10 dimethacrylate, bisphenol A(EO)30 dimethacrylate,1,3-butyleneglycol dimethacrylate, polyethylene glycol 400dimethacrylate, polyethylene glycol 200 dimethacrylate, PPG1000(EO)15dimethacrylate, PPG1000(EO)3 dimethacrylate, trimethylolpropanetrimethacrylate, benzyl acrylate, lauryl acrylate, isodecyl acrylate,phenol(EO) acrylate, phenol(EO)2 acrylate, phenol(EO)4 acrylate,phenol(EO)6 acrylate, tetrahydro furfuryl acrylate, nonyl phenol(EO)4acrylate, nonyl phenol(EO)8 acrylate, nonyl phenol(EO)2 acrylate,ethoxyethoxy ethyl acrylate, stearyl acrylate, 1,6-hexandiol diacrylate,1,6-hexandiol(EO) diacrylate, butanediol diacrylate, hydroxy pivalicacid neopentyl glycol diacrylate, tripropylene glycol diacrylate,dipropylene glycol diacrylate, bisphenol A(EO)4 diacrylate, bisphenolA(EO)3 diacrylate, tricyclodecane dimethanol diacrylate, tetraethyleneglycol diacrylate, polyethylene glycol 400 diacrylate, polyethyleneglycol 200 diacrylate, polyethylene glycol 300 diacrylate, polyethyleneglycol 600 diacrylate, polypropylene glycol 400 diacrylate,polypropylene glycol 750 diacrylate, bisphenol A(EO)10 diacrylate,bisphenol A(EO)30 diacrylate, tris(2-hydroxy ethyl)isocyanuratediacrylate, trimethylolpropane triacrylate, trimethylolpropane(EO)3triacrylate, trimethylolpropane(EO)6 triacrylate,trimethylolpropane(EO)9 triacrylate, trimethylolpropane(EO)15triacrylate, glycerin propoxylated triacrylate, pentaerythritoltriacrylate, trimethylolpropane(PO)3 triacrylate, tris(2-hydroxyethyl)isocyanurate triacrylate, pentaerythritol n-EO tetraacrylate,pentaerythritol tetraacrylate, dipentaerythritol pentaacrylate,dipentaerythritol hexaacrylate, caprolactone acrylate, O-phenylphenol EOacrylate, and methylene bisacrylamide.

In some embodiments, the hydrogel precursor solution includes one ormore of the following, optionally as functionalizing agents andmolecular recognition agents: phenylboronic acids and derivativesthereof, aptamers including oligonucleotides and peptide molecules, andother chelating agents for sensing a wide range of analytes, includingbiomolecules such as proteins, DNR, and RNA. Non-limiting examples ofsuch functionalizing agents include, without limitation,3-(acrylamido)-phenylboronic acid (3-APBA), 3-aminophenylboronic acid,5-amino-2-fluorophenylboronic acid, 4-amino-3-fluorophenylboronic acid,peptides, antibodies, concanavalin A, glucose oxidase, glucosedehydrogenase, hexokinase, glucose/galactose-binding protein, a proteinand/or a fragment functionally equivalent to a protein, a mutant ofhexokinase, a mutant of glucose/galactose-binding protein, a borateester derivative, and the like.

In some embodiments, the sensitivity and/or response time of thehydrogel sensor and thus of the fiber optic probe can be modulated byvarying at least one of the following: the content of the crosslinkingagent (e.g., to tune the elasticity of the resulting hydrogel sensor),the content of at least one monomer (e.g., to tune selectively thesensing range), and the content of the at least one photoinitiator. Forexample, the amount of the crosslinking agent included in the hydrogelprecursor solution can range from greater than 0% by weight to about 80%by weight, or any incremental value or subrange between that range. Insome embodiments, the amount of the monomer included in the hydrogelprecursor solution can range from about 0 to about 80% by weight, or anyincremental value or subrange between that range. In some embodiments,the amount of photoinitiator included in the hydrogel precursor solutioncan range from about 0% to about 80% by weight, or any incremental valueor subrange between that range. Unless otherwise provided, allpercentages by weight are based on the total weight of the solution. Insome embodiments, the sensitivity and/or responsive time of the hydrogelsensor can be modulated by including an additional monomer to form acopolymer.

In step (b), an end portion of the optical fiber is contacted with thedeposited polymeric precursor solution. For example, in someembodiments, an end portion of an optical fiber is contacted with alight-curable stimuli-responsive hydrogel precursor solution depositedon the substrate mold. The contacting can be performed by bringing theend portion of the optical fiber and at least a portion of the depositedpolymeric precursor solution into physical contact, or immediate orclose proximity. The contacting should be sufficient to permitattachment of the hydrogel sensor to the end of the optical fiberfollowing step (c). Any of the optical fibers of the present disclosurecan be utilized herein. For example, in some embodiments, the opticalfiber is a biocompatible fiber. In some embodiments, the optical fiberis a UV-curable biocompatible fiber formed in accordance with themethods disclosed herein as described in more detail below. In someembodiments, the end portion of the optical fiber is silanized prior tobeing contacted with the deposited polymeric precursor solution. Thesilanized end of the optical fiber can be used to form covalent bondsbetween the optical fiber and the stimuli-responsive hydrogel. In someembodiments, crosslinking agents are utilized to attach thestimuli-responsive hydrogel and the optical fiber.

In step (c), the end portion of the optical fiber and the depositedpolymeric precursor solution are exposed to light. Any wavelength oflight suitable for carrying out the polymerization can be utilizedherein. For example, in some embodiments, the end portion of the opticalfiber and the deposited polymeric precursor solution are exposed toultraviolet light. The duration of the exposure to light generally andin particular to ultraviolet light is not particularly limited. Forexample, in some embodiments, the exposure duration or cure duration isabout 5 minutes. In some embodiments, the exposure duration or cureduration is about 60 minutes. In some embodiments, the exposure durationor cure duration is at least about 5 or about 15 seconds or longer.Other wavelengths of light can be utilized herein. For example, in someembodiments, the wavelengths of light used for curing include, withoutlimitation, gamma-radiation, X-rays, microwaves, etc. Alternatively, insome embodiments, the end portion of the optical fiber and the depositedpolymeric precursor solution can be exposed to a heat treatment, amongother treatments, to carry out the polymerization.

As described above, the surface of the substrate mold can include theinverse structure of the asymmetric microlens array that is to beimprinted on the stimuli-responsive polymeric material and used as thesensor component of the fiber optic probe. For example, in someembodiments, the substrate mold has a surface including an inverseasymmetric microlens array. In some embodiments, the substrate mold isreplica diffuser, wherein the inverse structure of the asymmetricmicrolens array formed on the surface of the substrate mold is replicamolded from a master light diffuser.

For example, FIG. 4 is a flowchart of a method of fabricating a replicadiffuser (e.g., the substrate mold) from a master light diffuser,according to one or more embodiments of the invention. As shown in FIG.4, the method can comprise depositing 402 a light curable prepolymersolution on a master light diffuser. The master light diffuser caninclude a master asymmetric microlens array, which can be used as atemplate or mold to form the inverse asymmetric microlens array on thesubstrate mold. The depositing can be performed by drop-casting,pipetting, or coating the light curable prepolymer solution on themaster light diffuser. The light curable prepolymer solution can includeone or more of oligomers, monomers, photoinitiators, coinitiators,crosslinking agents, stabilizers, and plasticizers, including any ofthose disclosed herein. Usually, the prepolymer solution should beselected such that the resulting polymer is one which can be used as areplica diffuser without adverse interactions with thestimuli-responsive polymeric material. For example, the prepolymersolution should be selected such that, when the replica diffuser is usedto imprint an asymmetric microlens array on a stimuli-responsivepolymeric material, the resulting sensor component can be released orpeeled from the replica diffuser without causing any damage thereto.This can be achieved by selecting materials which will not strongly bindor irreversibly bind with stimuli-responsive polymeric materials (e.g.,by selecting materials that do not bind or at least reversibly bind withmaterials used to form the sensor component). In some embodiments, thelight curable prepolymer solution is ultraviolet light curable. Forexample, UV curable acrylics, such acrylated epoxies, acrylatedpolyesters, acrylated urethanes, acrylated silicones, and the like, canbe utilized herein. Other light curable polymeric materials can be used,including those described elsewhere herein. In step 404, the lightcurable prepolymer solution is exposed to light to cure the prepolymer(e.g., cause polymerization therein). In step 406, the cured polymer isreleased or peeled from the master light diffuser to obtain thesubstrate mold (or replica diffuser) including the inverse asymmetricmicrolens array. In some embodiments, the releasing or peeling in step406 can involve the use of a solvent. In some embodiments, mechanicalseparation is sufficient to separate the substrate mold from the masterlight diffuser.

Referring now to FIG. 5, a flowchart of a method of fabricating anoptical fiber is provided, according to one or more embodiments of theinvention. As shown in FIG. 5, the method 500 can comprise injecting 502a light curable prepolymer solution into a tubular body; exposing 504the light curable prepolymer solution to light to cure the prepolymer(e.g., to cause polymerization therein); and extracting 506 apolymerized optical fiber from the tubular body. Any of the lightcurable polymeric materials and precursors of light curable polymers ofthe present disclosure can be utilized herein. In some embodiments,precursors of ultraviolet light curable polymers are injected into thetubular body. In some embodiments, the light curable prepolymer solutionincludes prepolymers or precursors of an ultraviolet light curablepolymer that is biocompatible and thus form biocompatible opticalfibers. For example, in some embodiments, the optical fiber is abiocompatible hydrogel fiber. In some embodiments, the optical fiber isa biocompatible polymeric fiber. In some embodiments, the polymerizedoptical fiber is extracted in step 506 by applying water pressure. Insome embodiments, the polymerized optical fiber is extracted in step 506by applying air pressure. Other gases and liquids can be utilized hereinfor extracting the polymerized optical fiber and thus these examplesshall not be limiting. In some embodiments, the method 500 furthercomprising forming one or more layers surrounding the polymerizedoptical fiber. For example, in some embodiments, the layer has a lowerrefractive index than the polymerized optical fiber and thus can be usedas cladding.

Referring now to FIG. 6, a schematic diagram of a system 600 configuredfor operation in transmission mode is shown, according to one or moreembodiments of the invention. In the illustrated embodiment, the system600 includes a fiber optic probe 602. A proximal end 604 of the fiberoptic probe 602 is coupled to a light source 608 which can be configuredto transmit either monochromatic light or broadband light through thefiber optic probe 602. A distal end portion 606 of the fiber optic probe602 includes a sensor component 610 which as described above includes anasymmetric microlens array imprinted on a stimuli-responsive polymer. Alight detector 612 is disposed proximally to the distal end portion 606of the fiber optic probe 602 such that at least a portion of the lighttransmitted from the asymmetric microlens array is incident upon thelight sensor 612. Advantageously, an optical power meter or a smartphonecan be used as the light sensor 612. During operation, the distal endportion 606 of the fiber optic probe 602 comprising the sensor component610 can be exposed to an environment 614 and the maximum opticaltransmitted power recorded by the light sensor 612 can be correlated tothe property being sensed.

Referring now to FIG. 7, a schematic diagram of a system 700 configuredfor operation in reflection mode is shown, according to one or moreembodiments of the invention. In the illustrated embodiment, the system700 includes a fiber optic probe 702. A proximal end 704 of the fiberoptic probe 702 is coupled to a light source 708 via a first terminal709 (e.g., an input terminal) of a coupler 707 and to a light sensor712, such as an optical power meter, via a second terminal 713 (e.g., anoutput terminal) of the coupler 707. The coupler 707 can include aplurality of optical fibers, at least one of which is used fortransmitting light from the light source 708 and one or more of which isused for guiding reflected light to the light sensor 712. A distal endportion 706 of the fiber optic probe 702 includes a sensor component710, the sensor component 710 having an asymmetric microlens arrayimprinted on a stimuli-responsive polymeric material. During operation,the distal end portion 706 of the fiber optic probe 702 comprising thesensor component 710 can be exposed to an environment 714 and themaximum optical reflected power recorded by the light sensor 712 can becorrelated to the property being sensed.

In some embodiments, a system is provided, wherein the system comprisesa fiber optic probe including an optical fiber and a stimuli-responsivematerial, wherein the stimuli-responsive material has a first surfaceattached to the optical fiber and a second surface patterned with anasymmetric microlens array; a light source coupled to the fiber opticprobe, wherein the light source is configured to transmit light throughthe optical sensor; and a light sensor for detecting light transmittedthrough the asymmetric microlens array or light reflected from theasymmetric microlens array.

In some embodiments, a system is provided, the system comprising a fiberoptic probe including an optical fiber and a sensor component attachedto the optical fiber, the sensor component including an asymmetricmicrolens array imprinted on a stimuli-responsive hydrogel; a lightsource coupled to the fiber optic probe, wherein the light source isconfigured to transmit light through the optical sensor; and a lightsensor for detecting light transmitted through the asymmetric microlensarray or light reflected from the asymmetric microlens array.

According to one or more embodiments, fiber optic probes comprisingalcohol-responsive hydrogel sensors are provided. The fiber optic probesdisclosed herein can be used for determining the volumetric modulationof stimuli-responsive polymers in real time. Asymmetric microlensstructures (light diffusing microstructures) were imprinted onalcohol-responsive hydrogels during a UV curing process and used asstand-alone hydrogel sensors or chemically attached to the ends ofsilica and biocompatible optical fibers to form fiber optic probes.(FIGS. 8A-8C). Quantitative measurements were carried out using asmartphone to demonstrate the ease, simplicity, and practicality of thereadout methodology. To demonstrate the utility in real-time sensing,the fiber optic probe was evaluated in various concentrations ofethanol, propan-2-ol, and dimethyl sulfoxide. To develop biocompatibleprobes for physiological applications, an asymmetric microlensarray-imprinted polymer was attached to the end of a hydrogel opticalfiber. The developed hydrogel fiber probes may have application inpoint-of-care diagnostics, continuous biomarker monitoring, and criticalcare sensing devices.

The stand-alone alcohol sensor was constrained on a glass slide and wasevaluated in solutions having alcohol concentrations ranging from 0-50vol %. The stand-alone sensor was equilibrated in DI water beforetesting and solutions containing various concentrations of ethanol,propan-2-ol, and DMSO were prepared. The sensor was submerged in DIwater (1 ml) and was illuminated with a green laser of wavelength 532 nm(FIG. 9A). The spatial profile of the optical transmitted power (S_(t))was recorded by an optical power meter and was taken as the reference.The DI water was replaced with an aqueous ethanol solution (2 vol %, 1ml), and the S_(t) was recorded again. The ethanol solution (2 vol %)was replaced by higher ethanol concentration (4 vol %), and the readingwas recorded; this protocol was repeated until reaching an alcoholconcentration of 50 vol % (FIG. 9B). The same procedure was followed toexamine the sensor's sensitivity to propan-2-ol and DMSO.

The optical transmitted power from the sensor exhibited a Gaussianprofile. An increase in the maximum optical transmitted powers (P_(t))was observed with increasing alcohol concentration. While not wishing tobe bound to a theory, it is believed that this trend was observed due todecreasing scattering angles resulting from decreasing the diffusionefficiency of the microlens structures, thereby concentrating thetransmitted power on a smaller solid angle and thus leading to a smallercircular area on the projection screen/photodiode sensor (FIGS. 9B-9D).The P_(t) readings as a practical readout method were utilized tomonitor the alcohol concentrations. The sensor responded to all thepresented alcohols; however, it was more sensitive to DMSO as comparedto propan-2-ol and ethanol, this was likely due to DMSO penetrating thehydrogel network (FIG. 9E). For example, the ability of an alcohol topenetrate and/or diffuse into a hydrogel matrix can increase when thealkyl chain length increases. The sensor's response to ethanol wasnonlinear, with a sensitivity of ˜4 μW vol %⁻¹ for low ethanolconcentrations in the range of 0-10 vol %, which increased to ˜6 μW vol%⁻¹ for higher concentrations in the range of 10 to 40 vol %, andreached ˜20 μW vol %⁻¹ for ethanol concentrations in the range of 40-50vol % (FIG. 9E). Further, the sensor's response to propan-2-ol waslinear, with a sensitivity of ˜7.3 μW vol %⁻¹ observed across the entireconcentration range of 0-50 vol %. In addition, the sensor's response toDMSO was nonlinear for the entire tested concentration range (0-50 vol%). The sensitivity increased from ˜8 μW vol %⁻¹ for concentrations inthe range of 0-10 vol %, to ˜12 μW vol %⁻¹ for concentrations in therange of 10-40 vol %, and to ˜13 μW vol %⁻¹ for higher concentrations inthe range of 40-50 vol % (FIG. 9E). The sensitivity of the hydrogel toalcohols could be controlled by varying the content of the cross linker;hence, the elasticity of the hydrogel film could be tuned. Unlikediffraction- and chromophore-based systems, the asymmetricmicrolens-based sensors disclosed herein were able to cover the entirealcohol concentration range 0-50 vol %.

For the remote sensing applications, the alcohol hydrogel sensor waschemically attached to an end of a multimode silica fiber having adiameter of 500 μm. The fabrication of the fiber optic probe includedpreparing a poly HEMA matrix which is an alcohol-responsive polymer,replicating the asymmetric microlens arrays, and attaching the hydrogelsensor to the end of the optical fiber. Advantageously, the fabricationwas achieved in one step via a simple process. Unlike fiber optic probesbased on Surface Plasmon resonance (SPR) or the interferometricspectroscopy, the fabrication process for the fiber optic probesdisclosed herein was facile and rapid. Additional advantages of thefabrication processes disclosed herein are that a multitude ofcomplicated steps can be avoided, such as pretreatment of the opticalfiber, depositing a thin metal layer (plasmonic coating), immobilizingthe hydrogel on the metal layer, and other stringent requirements suchas the need for high-quality films.

The fiber optic probe was tested for alcohol detection in thetransmission and reflection configurations. Optical microscope images ofthe silica fiber and photos of the fiber probe guiding different laserbeams are displayed in FIGS. 10B-10D. A green laser (532 nm) was coupledwith the functionalized silica fiber and the output signals (P_(t)) wererecorded by an optical power meter or a smartphone (FIG. 10A). Uponincreasing the alcohol concentration, the probe exhibited a linearresponse to propan-2-ol and nonlinear responses to ethanol and DMSO. Allresults were consistent with the results discussed above involving thesensor constrained on a glass substrate. The fiber optic probe exhibiteda higher sensitivity to DMSO than to propan-2-ol and ethanol. Startingfrom the identical P_(t) values of 390 μW at 0 vol %, the P_(t) recordedby the optical power meter showed an increase of ˜246, 273, and 500 μWat 50 vol % concentrations of ethanol, propan-2-ol, and DMSO,respectively (FIG. 10E). Similarly, the maximum transmitted luminance(L_(t)) recorded by the smartphone showed an increase of ˜ 181, 202, and370 Lux at 50 vol % concentrations of ethanol, propan-2-ol, and DMSO,respectively (FIG. 10F). Output signal trends recorded by the smartphoneand the optical power meter were analogous, confirming the reliabilityof the smartphone-based readout method. One of the multitude ofadvantages of the fiber optic probes disclosed herein is that theypermit a simple and direct readout process that does not require complexdata processing, expensive and bulky instrumentation, like computers.The fiber optic probes disclosed herein are compact and simple.Additionally, the fiber optic probes reduce the cost of the sensor byintroducing cost-effective and portable instruments for recording theoutput signals (e.g., a smartphone can be used). Further advantages ofthe fiber optic probes include their low limit of detection (2%, v/v)compared with conventional fiber optic probes that depend oninterferometry, Surface Plasmon resonance, Fresnel reflectometry, andtotal internal reflection phenomena. For instance, tapered fiber probeexhibit a LOD of 5% (v/v) for ethanol; Fabry-Periot fiber probes exhibita LOD of 10% (w/w) for ethanol; fiber probes based on Surface Plasmonresonance exhibit a LOD of 10% (v/v); and fiber probes based on Fresnelreflectometry principal exhibit a LOD of 30% (v/v) for ethanol. Alcoholfiber probe based on the change in the total internal reflectionexhibited higher LOD of 10% (v/v). Even colorimetric-responsivehydrogels based on inverse opal structure made of the samealcohol-responsive hydrogel (HEMA) showed LOD of 5% (v/v) for ethanoldetection.

For implantable biosensing applications, the fiber optic probes wereused in systems configured to operate in reflection mode. A broadbandwhite light source was coupled to one of the terminals at the bifurcatedside of a 2×1 coupler and the reflected power was collected from thesecond terminal at the same side using an optical power meter (FIG.10G). The functionalized end of the probe was submerged in variousalcohol concentrations. With increasing alcohol concentration, thehydrogel functionalized tip underwent a positive dimensional shift whichincreased the reflected power guided in the probe. At 50 vol % ethanol,propan-2-ol, and DMSO concentrations, maximum increases of ˜0.7, 1, and1.6 μW were recorded, respectively (FIG. 10H). The trend of the outputsignals in the reflection configuration was comparable to the trend inthe transmission configuration as the response of the fiber probe waslinear for propan-2-ol and nonlinear for ethanol and DMSO, in additionto the highest sensitivity being observed for DMSO and the lowest forethanol. The reusability of the fiber probe was examined by exposing thefiber probe to ethanol solution (5%, v/v) for six cycles (FIG. 10I). Thefiber probe was modulated over several cycles with limited random memoryretention. The response time was short, within a few seconds, and theequilibrium time was about 60 seconds, which varied depending on thealcohol type and alcohol concentration.

Continuous monitoring of pH levels in blood and brain tissue ofcritically ill patients and patients suffering from a traumatic braininjury is a primary medical exigency. The pH levels of the brain canindicate tissue viability and decreases during brain insult from thenormal pH 7.4 to 6.8. Additionally, continuous monitoring of the braintissue pH might be useful in the treatment of comatose neurosurgicalpatients. While electrochemical sensors have been developed,hydrogel-based fiber optic probes may present unique advantages overelectrochemical sensors as they are biocompatible for in vivo sensingand safer given that no electrical current is passed.

According to one or more embodiments, fiber optic probes comprisingpH-responsive hydrogel sensors are provided. The fiber optic probesdisclosed herein can be used for determining the volumetric modulationof stimuli-responsive polymers in real time. Asymmetric microlensstructures (light diffusing microstructures) were imprinted onpH-responsive hydrogels during a UV curing process and used asstand-alone hydrogel sensors or chemically attached to the ends ofsilica and biocompatible optical fibers to form fiber optic probes.(FIGS. 8A-8C). Quantitative measurements were carried out using asmartphone to demonstrate the ease, simplicity, and practicality of thereadout methodology. To demonstrate the utility in real-time sensing,the fiber optic probe was evaluated in solutions having varying pHlevels. The fiber probe showed a rapid response to pH in the acidicregion with a sensitivity of 40 nW pH⁻¹. To develop biocompatible probesfor physiological applications, a microlens array-imprinted polymer wasattached to the tip of a hydrogel optical fiber. The optical fiber probein the refection configuration showed a sensitivity of 7 nW pH⁻¹. Thedeveloped hydrogel fiber probes may have application in point-of-carediagnostics, continuous biomarker monitoring, and critical care sensingdevices.

Asymmetric microlens structures (light diffusing microstructures) wereimprinted on pH responsive-hydrogels during a UV curing process tocreate stand-alone and fiber integrated sensors (FIGS. 8A-8C). Thestand-alone hydrogel pH sensor imprinted with the asymmetric microlensarray and constrained on a glass slide was tested in transmission modein various pH solutions (4.3-8.8) of ionic strength (150 mM) at 24° C.The sensor was submerged in pH solution (1 ml) and was illuminated witha laser beam (532 nm) and S_(t) was recorded by an optical power meter.The sensor's volume experienced a positive shift with increasing pH ofthe solution due to the Donnan's potential resulting from ionization ofthe carboxyl group and dissolving of the carboxylates. Accordingly, thelight diffusing efficiency of the sensor decreased, thus increasingP_(t) on account of the forward scattering angle (FIG. 11A). Initially,the pH sensor significantly responded to pH level in the range of 5.0 to7.0, with responses hard to detect in the alkaline region, where theoutput signal increased by ˜1.7 μW (40%), as it increased from 4.2 μW to5.9 μW upon increasing pH from 5.0 to 7.0 (FIG. 11B). When the pH waschanged from 4.3 to 5.0, the sensor's output signal changed by ˜8%,consistent with the pH sensor based on poly HEMA. The hydrogel pH sensorshowed a similar response in the reflection mode as compared with thetransmission mode, where the output signal significantly increased by˜19% with increasing pH from 5.0 to 7.0, and no response was recordedabove pH 7.0 (FIG. 11D). The output signal changed by 1.5% when pH wasincreased from 4.3 to 5.0. The decrease of the sensor's sensitivity inthe reflection mode was be attributed to the readout setup, where thesensor was illuminated at 45° and the detector was fixed at the sameangle (FIG. 11C).

The hydrogel sensor was chemically attached to the tip of a silicaoptical fiber following the same protocol utilized to attach the alcoholsensor. The sensing investigations were carried out in both transmissionand reflection modes (FIG. 11E). The response of the fiber optic probeto pH was comparable to the response of the constrained pH hydrogelsensor attached to the glass substrate (FIG. 11F). The trends of theoutput signals recorded by the smartphone and the power meter were same(FIGS. 11F-11G). The fiber optic probe was very sensitive in the pHrange from 5.0 to 7.0 and displayed negligible response above pH 7.0.The recorded L_(t) by the smartphone showed a change of ˜40% uponchanging the pH from 5.0 to 7.0, where a ˜2% output change correspondedto a 0.1 pH increment. The response of the pH fiber probe in thereflection configuration was analogous to the transmission mode (FIG.11H). An increase of 115 nW was measured in the output signal uponincreasing the pH from 5.0 to 7.0, with the sensitivity of ˜57 nW pH⁻¹.The fiber optic probe can be used for monitoring gastric pH which has aphysiological range of 1-7, and for milk quality application as the milkpH lies in the range of 4.6-6.7. The fiber optic probes can be utilizedin other applications, as the sensitivity of the fiber probe and thesensing range can be tailored by varying the ionizable co-monomer andits concentration. For example, to increase the sensitivity in thealkaline pH, the hydrogel network can be co-polymerized with2-(dimethylamino) ethyl methacrylate (pK_(a)=8.4).

A key challenge of the pH-sensitive fiber probes for the real-timemeasurements in biological applications is the swelling and shrinkagekinetics. The response time of the fiber probe can depend on theconcentration of the ionizable monomer (AA) and the ionic strength ofthe examined solution, where the response time is directly proportionalto the ionizable monomer and inversely proportional to the bufferconcentration. The fiber optic probe disclosed herein showed a rapidresponse as it reached the equilibrium within 60±10 s when the pH waschanged from 5.5 to 6.0 and the output signal varied up to ˜17.6 μW(FIG. 11I). Additionally, the fiber probe was examined for reusabilityby exposing it to consecutive swelling/shrinkage for three cycles and nohysteresis was observed (FIG. 11J). This behavior was consistent withthe previous studies of polyHEMA-co-AA where the hydrogel sensor did notpresent a significant hysteresis in high ionic strength solution.

For the implantable biosensor applications, the silica fiber probe wasreplaced with a biocompatible fiber as the silica fiber causesinflammation in the implantation site and increases the risk ofinfection. The biocompatible fiber was made of polyethylene glycoldiacrylate, functionalized with the pH-responsive hydrogel, and wasexamined for pH sensing in physiological conditions (FIG. 11K). Thetrend of the output signals against pH was comparable to the response ofthe silica fiber optic probe. The response of biocompatible fiber opticprobe was considerable in the pH range of 5.0 to 7.0 and reached aplateau above pH 7.0. The sensitivity of the probe was ˜10 nW pH⁻¹ inthe pH range of 5.0 to 7.0 which is slightly less than that observed forthe silica fiber optic probe and is likely due to inefficient lightguiding of the biocompatible core bare fiber. This can be overcome bydecreasing the guided light loss which can be achieved by covering thefiber core with a biocompatible clad having a low refractive index.

In contrast to fiber optic probes based on interferometric techniques,the developed fiber optic probes comprising hydrogel sensors imprintedwith asymmetric microlens arrays do not require high quality films,coherent light sources, and complex and bulky readout setups. Ascompared to the SPR probes that require multistage and complicatedfabrication processes, complex output signal processing, and costlyinstrumentation setups to obtain readouts, the asymmetric microlensarray fiber optic probes disclosed herein can be fabricated via a simplesingle-stage process. In addition, the fiber optic probes disclosedherein are low-cost and portable. Unlike fluorescent probes, themeasurement of the optical power is not prone to photobleaching and thecorresponding shortcomings thereof. Additionally, the asymmetricmicrolens array increases the sensor's active area which enhances thediffusion rate of the analyte into the responsive-hydrogel, shorteningsensor response time. The developed fiber optic probes can befunctionalized with any of a wide array of stimuli-responsive hydrogelsto sense glucose, proteins, nucleic acids, etc. and can also be utilizedin drug delivery applications.

According to one or more embodiments, fiber optic probes are thusprovided for remote sensing and implantable biosensing applicationsinvolving alcohol and varying pH levels. As described above, alcohol-and pH-responsive hydrogels were imprinted with asymmetric microlensarrays during a UV-curing process and were attached to the ends ofoptical fibers. Firstly, the alcohol and pH hydrogel sensors constrainedon glass slides were interrogated in the transmission and reflectionconfigurations. An optical power meter and a smartphone were employedfor recording the output signals, which showed an analogous trendconfirming the reliability of using the smartphones to simplify thereadout methodology. Secondly, the fiber optic probes based on alcohol-and pH-responsive hydrogels showed similar responses to their hydrogelsensor counterparts constrained on glass slides irrespective of whetherthey were utilized in transmission mode or reflection mode. In addition,the biocompatible fiber optic probe showed an analogous response to thesilica fiber probe; however, the biocompatible fiber showed lesssensitivity, presumably due to light loss. The fiber optic probes, andrelated methods, bypass numerous steps involved in typical fabricationprocesses of conventional fiber optic probes based on hydrogels andoffers economical cost and portable readout strategies for reducingoperating costs of fiber optic probes. The developed sensors havedemonstrable and/or promising applications in biological sensing,point-of-care diagnostics, as well as critical care devices forreal-time measurements.

Continuous glucose monitoring can enable strict control of blood glucoseconcentration in diabetic and intensive care patients. Optical fibershave emerged as an attractive platform; however, their practicalapplications are hindered due to lack of biocompatible fiber materials,complex and impractical readout approaches, slow response times, andtime-consuming fabrication processes.

According to one or more embodiments, fiber optic probes comprisingglucose-responsive hydrogels are provided. The fiber optic probes can beused for continuous and/or intermittent glucose monitoring underphysiological conditions. The quantification of glucose was demonstratedusing smartphone-integrated fiber optic probes that overcome existingtechnical limitations. The fiber optic probes include aglucose-responsive hydrogel that was imprinted with an asymmetricmicrolens array, attached to the end of a multimode silica optical fiberduring photopolymerization, and used as a sensor for glucose sensingunder physiological conditions. A smartphone and an optical power meterwere employed to record the output signals. The fiber optic probesshowed high sensitivity (2.6 μW mM⁻¹), rapid response times, and highglucose selectivity in the physiological glucose range. In addition, thefiber optic probes attained glucose complexation equilibrium within 15min. The lactate interference was also examined and found to be minimal,˜0.1% in the physiological range. A biocompatible hydrogel made ofpolyethylene glycol diacrylate was utilized to fabricate a flexiblebiocompatible hydrogel fiber to replace the silica fiber, and the end ofthe biocompatible hydrogel fiber was functionalized with theglucose-sensitive hydrogel during the ultraviolet light curing process.The biocompatible optical fiber was quickly fabricated by the molding,the readout approach was facile and practical, and the response toglucose was comparable to the functionalized silica fiber. Thefabricated optical fiber sensors may have applications in wearable andimplantable point-of-care and intensive-care continuous monitoringsystems.

The fiber optic probes included a glucose recognition agent. The glucoserecognition agent (3-(acrylamido)-phenylboronic acid) was crosslinkedwith acrylamide to create glucose-responsive hydrogel and an asymmetricmicrolens array (light diffusing microstructures) was imprinted on thehydrogel. The glucose-responsive hydrogel was chemically attached to thetip of a silica multimode fiber during the photopolymerization process.The functionalized fiber was interrogated for glucose quantification intransmission mode and reflection mode. Upon glucose complexation withthe boronic acid groups immobilized in the hydrogel matrix, the hydrogelattached to the optical fiber shifted volumetrically, altering thecurvatures of the imprinted asymmetric microlens array. The transmittedand the reflected optical powers of the functionalized fiber weremeasured by an optical power meter and a smartphone. In addition, thehydrogel sensor was attached to the end of a biocompatible hydrogelfiber. The biocompatible functionalized fiber was flexible and offeredthe convenience to be potentially implemented or implanted in biologicaltissues. The glucose-responsive fiber optic probe disclosed herein hasadditional advantages over the previously developed fiber optic probes,such as an easy readout process due to its compatibility withsmartphones and the ability to provide readouts without output signalprocessing, rapid response times (e.g., about 30 s), short equilibriumtimes (e.g., about 15 min), and low-cost, glucose-selective,plug-and-play technology.

In some embodiments, the glucose-responsive hydrogel was fabricated,functionalized with 3-APBA, and stamped with asymmetric microlens arraysduring photopolymerization (FIG. 12A). Distribution of the asymmetricmicrolens array and the optical microscope image are displayed in FIGS.17A-17B. The stamped hydrogel sensor was attached to a commercialmultimode silica fiber and an in-house made biocompatible fiber duringthe polymerization process (FIGS. 12B-12C). Fabrication of thebiocompatible fibers is shown in FIG. 12D. The immobilized 3-APBA in thehydrogel matrix of the sensor had a high affinity to glucose moleculesforming anionic boronate due to 1:1 complexation in the hydrogelnetwork, increasing the osmotic Donnan pressure and causing acorresponding volumetric shift (FIG. 18). The volumetric shift of thehydrogel modified the curvature of the asymmetric microlens arraystamped on the hydrogel's surface leading to a change in the focallength of the microlenses and thus the maximum transmitted/reflectedpower that was correlated to the measured glucose concentration.

The glucose-responsive hydrogel sensor constrained on a glass substrateand stamped with an asymmetric microlens array was examined in variousglucose concentrations (0 to 50 mM). The sensor was equilibrated in PBSsolution (pH 7.4, ionic strength 150 mM, 24° C.) for 2 h before testing.A stock glucose solution (100 mM) was prepared in PBS buffer of pH 7.4and diluted using the PBS solution to prepare the required glucoseconcentrations. The sensor was submerged in glucose-free PBS buffersolution (1 ml) and illuminated with a green laser (532 nm) and thespatial profile of the transmitted power (SP_(t)) was recorded as areference (FIG. 13A). The glucose-free PBS buffer was replaced with abuffered glucose solution (1 ml, 5 mM), and the SP_(t) was recordedafter 15 min. The low glucose concentration (5 mM) was replaced with ahigher concentration (10 mM) and the reading was recorded after 15 min,and this protocol was repeated until reaching 50 mM. The recorded SP_(t)for the sensor in various glucose concentrations exhibitedGaussian-shaped profiles and the forward scattering angles decreasedwith increasing glucose concentrations. The diffused light formed a spothaving a smaller diameter on the screen, increasing the maximum opticaltransmitted power (P_(t)) with glucose concentration (FIG. 13B). TheP_(t) readings as a practical readout method were utilized to monitorthe glucose concentrations. The sensor's response saturated withincreasing glucose concentration; however, it exhibited a linearresponse within the range of 0-20 mM, which had a correlationcoefficient, R² of 0.99 (FIG. 13C). The P_(t) increased from 79.4 to86.7 μW when the glucose concentration increased from 0 to 10 mM, andreached 99 μW when the glucose concentration increased to 50 mM. Toconfirm the working principle, the surface morphology of the hydrogelsensor was investigated under the optical microscope while the sensorwas submerged in glucose-free PBS buffer and PBS buffer of 50 mM glucoseconcentration. Upon glucose-boron complexation, the sensor swelled inz-direction only as it was constrained on the glass slide. The surfaceprofile analysis showed that the depth of the microlens array was higherunder glucose-free condition as compared to the surface's depth inglucose condition. Again, the hydrogel sensor was examined for glucosesensing, but in this test, the sensor was illuminated by a broadbandwhite light beam and the output signals, the maxima transmittedilluminance (L_(t)), were measured by a smartphone (FIG. 13D). Thirdly,the sensor was interrogated in the reflection configuration as thesensor was illuminated by a monochromatic light (532 nm) at an incidentangle of 45° and the maximum reflected powers (P_(r)) of the diffusedbeam were collected using an optical power meter (FIG. 13D). The ambientlight sensor of a smartphone was utilized to record the output signalsto demonstrate the compatibility and the simplicity of the readoutprocess. The readout for the glucose-free buffer was 60 lux and jumpedup to 69 upon increasing glucose concentrating from 0 to 20 mM andreached to 75 lux at 50 mM (FIG. 13E). The relationship of the glucoseconcentration against the sensor's output signal was consistent with theexperiment carried out using the monochromatic light and the opticalpower meter (FIG. 13C). The sensor's response was linear for glucoseconcentration in the range of 0-20 mM with a correlation coefficient, R²of 0.99 and saturated at high glucose concentrations. The hydrogelsensor consistently detected glucose concentrations whether it wasilluminated by a monochromatic light or a broadband white light and thisis due to the ability of the microlenses array to control the beam shapeof the monochromatic and white light. In reflection configuration, theP_(r) increased with glucose concentration because of the positivevolumetric shift of the hydrogel sensor, decreasing the curvature of themicrolenses and consequently the light diffusion efficiency of thesensor (FIG. 13F). The sensor behavior was consistent with theexperiments that were carried out in the transmission mode (FIG. 13C).The P_(t) increased from 2.6 μW to 3.33 μW upon increasing glucoseconcentration to 20 mM and reached 3.88 μW at 50 mM (FIG. 13F). Thesensor's output signals saturated at a high glucose concentration (30mM) and the correlation coefficient had a linear relationship (R²=0.99)for glucose concentration within the range 0-20 mM.

For in vivo or remote glucose sensing applications, the hydrogel sensorwas attached to an end of a multimode silica fiber having a diameter of500 μm. The silica fiber with the hydrogel sensor attached thereto wasutilized for glucose detection in vitro in both transmission andreflection configurations. In transmission mode, the fiber optic probewas coupled to a monochromatic light source (532 nm) and the outputsignals (P_(t)) were recorded by either an optical power meter or asmartphone (FIG. 14A). Optical microscopy images of the fiber opticprobe's cross-section and photos of the fiber optic probe illuminated bydifferent monochromatic light sources (FIGS. 14B-14D). The fabricationprocess of the silica fiber optic probe included preparing the hydrogelmatrix, functionalizing the hydrogel with 3-APBA, imprinting thefunctionalized hydrogel with the asymmetric microlens array, andattaching the hydrogel sensor to the end of an optical fiber. Thesesteps were performed in a single step in about 5 min (FIG. 12B). Thisfacile and rapid fabrication approach is one of the great advantages ofthe developed hydrogel sensor in comparison to other fiber optic probessuch as fluorescent- and SPR-based probes. For instance, the preparationof the fluorescent glucose sensor requires multiple reaction stages andtime-consuming synthesis and purification steps. Similarly, thefabrication of the SPR fiber probes is complicated and requires manysteps, such as pretreatment of the optical fiber, decladding, depositinga thin metal layer, immobilizing the glucose sensitive layer, etc.

The fiber optic probe was tested in glucose concentrations ranging from0-50 mM and the P_(t) for each concentration over time was recorded at24° C. (FIG. 14E). When the glucose concentration was increased, thefiber optic probe's output signal (P_(t)) increased, showing a lineartrend with a correlation coefficient R² of 0.99 for glucoseconcentrations in the range of 5-20 mM. Upon increasing the glucoseconcentration from 0 to 20 mM, the P_(t) surged 48 μW, from 602 to 650μW (FIG. 14F). For high glucose concentrations ranging from 20 to 50 mM,the P_(t) increased 30 μW, indicating declined sensitivity. An 8.3%change was observed when the glucose concentration was increased from 0to 20 mM as compared to the 7% change over glucose concentrationsranging from 0-100 mM for conventional fiber probes. The fiber opticprobe was coupled to a green laser and re-interrogated for glucosesensing, except a smartphone was employed to measure the output signals.The maximum transmitted illuminance (L_(t)) increased by 69 Lux, from929 to 998 Lux with increasing glucose concentrations ranging from 0 to20 mM; however, the growth of the output signal was 49 Lux when theglucose concentration increased from 20 to 50 mM (FIG. 14G). The trendof the recorded L_(t) against the glucose concentrations was comparableto results recorded by the optical power meter. The fiber optic probe'sresponse was linear for glucose concentrations in the range of 5-20 mMwith a correlation coefficient R² of 0.99 and the sensitivity declinedat high concentrations as the sensor saturated. To test the feasibilityof utilizing the broadband white light for sensing as it is safer thanlasers for human body implantation sensing, the fiber optic probe wascoupled to a broadband white light source and re-examined for glucoseconcentrations in the range of 0-50 mM and the readout was collected bya smartphone and an optical power meter (FIG. 14H-14I). The trends ofthe output signals from the fiber optic probe immersed in variousglucose concentrations were comparable, irrespective of whether theoutput signals were recorded by the smartphone or the optical powermeter. The fiber optic probe's response decreased at highconcentrations. Below 30 mM, the response was linear with a correlationsensor's saturation at high glucose concentrations might be attributedto the limited availability of boronate binding sites and the reducedelasticity of the hydrogel matrix that competed with the volumetricswelling process. The fiber optic probe interrogation results weresimilar to those from previous experiments in which the hydrogel glucosesensor was constrained on a glass substrate. The fiber sensitivity was2.6 μW mM⁻¹ in the most significant glucose concentration range (5-20mM), calculated using the slope of the linear fit. The output signal ofthe fiber optic probe shifted by a coefficient R² of 0.99.Advantageously, the probe's response to glucose concentrations wassimilar when the coupled light source was a broadband white light or amonochromatic light source, and the smartphone was successfully employedfor readouts and showed a reliable response. The readout methodology wassimple and low cost whether the output signal was recorded by a powermeter or a smartphone. This is an advantage of the fiber optic probesdisclosed herein in comparison to other conventional glucose probes. Forinstance, interferometric, fluorescent, and SPR fiber probes requireprocessing of the output signal and high-cost instruments such asspectrophotometers and fluorometers for readout.

The silica fiber optic probe was also tested for glucose sensing withinthe concentration range of 0-50 mM in a reflection configuration, whichis the desired mode for in vivo glucose sensing. In the reflectionconfiguration, a three-terminal coupler 2×1 was utilized to connect thefiber optic probe with the white light source and the optical powermeter (FIG. 15A). The fiber optic probe was submerged in the glucosesolution (1 ml) and the optical reflected power (P_(r)) was recorded bythe optical power meter. Upon swelling of the hydrogel sensor attachedto the end of the optical fiber, the P_(r) guided in the optical fiberincreased (FIG. 15B). In reflection mode, the behavior of the outputsignal in response to changes in glucose concentrations was comparableto measurements obtained in transmission mode as the fiber response waslinear within the concentration range of 0 to 20 mM with a correlationcoefficient R² of 0.99, and the sensitivity decreased significantlyabove 20 mM. The optical reflected power was 318 nW for the glucose-freePBS buffer and increased to 338 nW at 20 mM concentration with asensitivity of 1 nW mM⁻¹ in this glucose range. For the high glucoseconcentration range of 20-50 mM, the output signal recorded an incrementof 13 nW.

The swelling dynamics of the fiber optic probe was studied at a constantglucose concentration (10 mM) as the P_(t) was recorded over time. Uponexposure of the fiber optic probe to the glucose solution, the bindingequilibrium (glucose-boron complexation) was saturated within 15 min andthe response time was 30 s (FIG. 15C). This equilibrium time wasone-third of the response times reported in previous studies, where thesaturation time for the 3-APBA-modified optical fiber was 45 min. Forthe diabetic patients, the readout rate required for monitoring glucoseconcentration is 0.078 mM·min⁻¹, and the proposed probe provided areadout rate of 0.66 mM min⁻¹, which is 8-fold higher than the requiredspeed. The stability and reusability of the silica fiber optic probewere investigated by detecting the response of the fiber optic probe infour complete and continuous cycles (FIG. 15D). The probe's response for10 mM glucose concentration was monitored for 15 min, followed by areset using an acetate buffer (pH 4.6) for ˜10 s, and maintained in PBSfor 15 min buffer before commencing the next cycle. When the probe wasimmersed in buffer at pH 4.6, the hydrogel sensor contracted due to thedecrease in the pH below the apparent pK_(a) value of theglucose-responsive hydrogel as the charged tetrahedral state of the3-APBA transformed to uncharged trigonal planar form releasing the boundglucose molecules. Upon immersing the functionalized tip into the PBSbuffer of pH 7.4, the attached hydrogel returned to it is originalvolume, and consequently the asymmetric microlens array was reset to itsoriginal geometry. These results are significant as the fiber opticprobe exhibited reusability with limited hysteresis and had comparablesensitivity for each cycle. The boronic acids bind to cis-diolcontaining molecules and α-hydroxy acids. Fructose and galactose aremonosaccharides present in human blood at low concentrations (<0.1 mM).In addition, there are many other sugars in blood in the form ofglycoproteins and macromolecular carbohydrates; however, they are notexpected to significantly interfere with the probe's response as theymay not diffuse into the hydrogel matrix and bind to PBA groups becauseof their large molecular sizes. Thus, the glucose selectivity during invivo sensing was expected to be minimal; however, lactate is present inblood at a concentration of 0.36-0.75 mM in healthy adults and has ahigh affinity to bind with phenylboronic acid by its α-hydroxy group.Thus, a potential interference of lactate on the probe's response wasinterrogated (FIG. 15E). The lactate solutions were prepared in PBSbuffer (pH 7.4) and the probe's response for lactate and glucose wererecorded separately at human body temperature (37° C.) to determine thepotential interference of lactate under the physiological conditions.The recorded output signals (P_(t)) of the fiber optic probe shiftedsignificantly at high lactate concentrations, but subtly any responsewas recorded at low lactate concentrations (1.0 mM). On the contrary,the output signal of the fiber optic probe considerably shifted at lowglucose concentrations within the physiological range (4.0-8.0 mM) andthe probe's response saturated at higher concentrations. At a lactateconcentration of 5.0 mM, the output signal increased by 1.2% over 15 minas compared to 4% increase for the same concentration of glucose in thesame interval. Therefore, the interference of the lactate according toits concentrations in blood would be 0.08%-0.17%. However, the smallmolecular weight (Mw: 90 g mol⁻¹) of lactate molecule accelerated itsdiffusion into the hydrogel matrix and its high affinity to bind withthe pendant phenylboronic acid, it has a limited potential interferencein the probe's response.

The effect of pH on the probe's response was examined as the probe wassubmerged in various pH solutions having the same ionic strength (150mM) at 24° C. and the P_(t) was recorded (FIG. 15F). Increasing the pHinduced a positive volumetric shift leading to an incremental change ofthe recorded P_(t). The probe's response for glucose detection candepend on the pH of the solution. The measured P_(t) increasedsignificantly starting from pH 6, which was due to swelling of theattached hydrogel sensor, caused by an increase in the anionic boronateions in the hydrogel network. Decreasing the pH below 6 slightly shiftedthe output signal, indicating a tenuous growth in the anionic boronateions. Furthermore, the effect of temperature on the fiber probe'sresponse was investigated within the range of 10−45° C. Raising thesolution temperature caused the glucose-responsive hydrogel to shrink orcontract, enhancing the curvature of the imprinted microlenses, andconsequently the output signal decreased. Within the temperature rangeof 20-35° C., the fiber probe's signal slightly shifted, whereas theoutput signals changed considerably below 20° C. and above 35° C. Theoutput signal shifted by 2% when the temperature increased from 10 to20° C., 0.5% with increases from 20 to 35° C., and 3.6% with increasesto 45° C. (FIG. 15G). The fiber optic probe's response to glucose can becalibrated at physiological conditions to avoid the temperature and pHinterferences.

Silica fiber optic probes are not compatible with biological tissues tobe implemented for in vivo sensing as they can cause inflammation at theimplanted sites and discomfort to patients. Therefore, a biocompatiblehydrogel fiber was fabricated to replace the silica fiber. Abiocompatible polymer, polyethylene glycol diacrylate (PEGDA), wasutilized to fabricate hydrogel optical fibers because PEGDA hydrogelcounters the adsorption of proteins such as fibrinogen, albumin, andfibronectin that host the inflammatory cell interactions. Initially,polymerized PEGDA cubes of 1 cm side length were prepared at precursorconcentrations of 5-90 vol % to determine the optimum concentrations forfabricating the hydrogel fiber (FIG. 16A). The hydrogel attenuation formonochromatic light (532 and 650 nm), and broadband white light wereinvestigated. For monochromatic and white light, increasing the PEGDAconcentration from 5 to 60 vol % considerably reduced the lightattenuation, and above 60 vol % a slight change was detected (FIGS.16B-16C). For monochromatic light, the attenuation was 22 dB cm⁻¹ at theprecursor concentration of 10 vol % and decreased to ˜1 dB cm⁻¹ when theprecursor concentration reached 50 vol %. The attenuation decreased to˜0.4 dB cm⁻¹ with increasing the precursor concentration to 90 vol %.These results confirmed that the optical properties of the PEGDAhydrogel depended on the precursor concentration. The attenuation of thebroadband white light measurements showed higher attenuation for shortwavelengths besides the significant dependence of the attenuation on theprecursor concentration. Considering the mechanical and opticalproperties, the hydrogel fiber was made using a PEGDA precursorconcentration of 60 vol %. The end of the hydrogel optical fiber wasfunctionalized with the glucose-responsive hydrogel as in the case ofthe silica fiber. The hydrogel fiber with a length of 5 cm and adiameter of 950 μm, was coupled with a broadband white light source andan optical power meter by the 2×1 coupler. The hydrogel fiber opticprobe was interrogated for glucose sensing in reflection mode and thereadings were recorded after 15 min for each glucose concentration. Theoutput signal increased by 17 nW for glucose concentrations in the rangeof 0-20 mM and by 10 nW for glucose concentration changes from 20-50 mM,presenting an analogous response to the silica fiber optic probediscussed above (FIG. 16D). The trend of the output signal was linearfor the glucose concentration range of 0 to 20 mM and above thisconcentration the sensitivity decreased considerably. Notably, thesensitivity of the hydrogel fiber optic probe was less than the silicafiber optic probe which might be attributed to the higher light loss inthe hydrogel fiber as compared to the silica fiber, and which can beimproved by cladding the hydrogel fiber with a low-refractive indexmaterial such as calcium alginate.

Fiber optic probes are thus provided for continuous glucose monitoringbased on hydrogel sensors attached to the ends of silica optical fibersand biocompatible hydrogel optical fibers. The hydrogel sensors could befunctionalized during the photopolymerization of the glucose-responsivehydrogel. The fabrication process of the fiber optic probe involvedpreparing the hydrogel, replicating the asymmetry microlens array,incorporating the 3-(acrylamido)phenylboronic acid, and attaching thehydrogel sensor to the end of the optical fiber. This process wasexecuted in 5 min. The facile and rapid fabrication process is anadvantage of the proposed fiber optic probe for glucose sensing. ThePEGDA hydrogel was utilized to fabricate a biocompatible optical fiberthat can potentially minimize the inflammation in the probe insertionsite. The fiber optic probe's readout was simple, practical, and lowcost as it did not require data processing or costly equipment. Theoutput signals were recorded by either a smartphone or an optical powermeter, utilizing broadband white light or monochromatic light sourcesfor illuminating the probe. Glucose quantification tests were attainedin both transmission and reflection configurations, and effect of pH andtemperature on the probe's response was also examined. The silica fiberoptic probe was highly sensitive and selective for glucose over lactatewithin the physiological range as the interference of lactate wastrivial (˜0.1%). The developed probe presented significant optical,mechanical, and practical advantages than their previous counterparts interms of ease fabrication process, rapid response, and practicalreadouts. The fiber optic probes thus can be used for applicationsinvolving in vivo glucose monitoring systems at point-of-care andintensive care units. To realize broader applications, the proposedfiber probe can be functionalized with chelating agents and aptamers forcontinuously sensing a wide range of biomolecules such as proteins, DNA,and RNA in clinical samples.

Discussion of Possible Embodiments

According to one aspect, a fiber optic probe can include an opticalfiber, and a sensor component attached to the optical fiber, the sensorcomponent including light diffusing microstructures (asymmetricmicrolens array) imprinted on a stimuli-responsive hydrogel.

The fiber optic probe of the preceding paragraph can optionally include,additionally, and/or alternatively, any one or more of the followingfeatures, configurations, and/or additional components.

In some aspects, the optical fiber is a biocompatible hydrogel fiber.

In some aspects, the asymmetric microlens array includes one or moremicrolenses, each of the one or more microlenses independently having aconvex aspherical surface, a plano-convex aspherical surface, aconvex-concave aspherical surface, a convex spherical surface, aplano-convex spherical surface, or a convex-concave spherical surface.

In some aspects, the asymmetric microlens array has at least one of thefollowing characteristics: microlenses which are non-uniformly spacedapart; microlenses which are arranged in a non-periodic configuration;microlenses which are arranged in a non-ordered configuration; at leasttwo microlenses having different surface topologies; at least twomicrolenses having different base geometries; and at least twomicrolenses having different heights.

In some aspects, the sensor component includes a glucose-responsivehydrogel.

In some aspects, the glucose-responsive hydrogel sensor includesacrylamide; N,N′-methylenebisacrylamide; 3-(acrylamido)-phenylboronicacid (3-APBA); and 2,2-dimethoxy-2-2phenylacetophenone (DMPA).

In some aspects, the sensor component includes an alcohol-responsivehydrogel.

In some aspects, the alcohol-responsive hydrogel sensor includes2-hydroxyethylmethacrylate (HEMA); ethylene glycol dimethacrylate(EGDMA); and 2,2-dimethoxy-2-phenylacetophenone (DMPA).

In some aspects, the sensor component includes a pH-responsive hydrogel.

In some aspects the pH-responsive hydrogel sensor includes2-hydroxyethylmethacrylate (HEMA); ethylene glycol dimethacrylate(EGDMA); acrylic acid (AA); and 2,2-dimethoxy-2-phenylacetophenone(DMPA).

According to a further aspect, a method of fabricating a fiber opticprobe can include (a) depositing a light-curable stimuli-responsivehydrogel precursor solution on a substrate mold having a surfaceincluding an inverse asymmetric microlens array; (b) contacting an endportion of an optical fiber with the light-curable stimuli-responsivehydrogel precursor solution deposited on the substrate mold; and (c)exposing the end portion of the optical fiber and light-curablestimuli-responsive hydrogel precursor solution to light to form astimuli-responsive hydrogel sensor imprinted with an asymmetricmicrolens array and attached to the end portion of the optical fiber.

The method of fabricating a fiber optic probe of the preceding paragraphcan optionally include, additionally, and/or alternatively, any one ormore of the following features, configurations, and/or additionalcomponents.

In some aspects, the light-curable stimuli-responsive hydrogel issynthesized, imprinted with the asymmetric microlens array, and attachedto the end portion of the optical fiber in step (c).

In some aspects, the light-curable stimuli-responsive hydrogel precursorsolution includes at least the following: a monomer, a crosslinkingagent, and a photoinitiator.

In some aspects, the substrate mold is fabricated by depositing alight-curable prepolymer solution on a master light diffuser having asurface including a master asymmetric microlens array; exposing thedeposited light-curable prepolymer solution to light to cure theprepolymer; and releasing the cured prepolymer from the master lightdiffuser to obtain the substrate mold, the substrate mold including theinverse asymmetric microlens array.

In some aspects, the optical fiber is fabricated by: injecting alight-curable monomer solution into a tubular body; exposing the monomersolution to light to initiate polymerization; and extracting apolymerized fiber from the tubular body to obtain the optical fiber.

In some aspects, the asymmetric microlens array includes one or moremicrolenses, each of the one or more microlenses independently having aconvex aspherical surface, a plano-convex aspherical surface, aconvex-concave aspherical surface, a convex spherical surface, aplano-convex spherical surface, or a convex-concave spherical surface.

According to another aspect, a system can include a fiber optic probeincluding an optical fiber and a sensor component attached to theoptical fiber, the sensor component including an asymmetric microlensarray imprinted on a stimuli-responsive hydrogel; a light source coupledto the fiber optic probe, wherein the light source is configured totransmit light through the optical sensor; and a light sensor fordetecting light transmitted through the asymmetric microlens array orlight reflected from the asymmetric microlens array.

The system of the preceding paragraph can optionally include,additionally, and/or alternatively, any one or more of the followingfeatures, configurations, and/or additional components.

In some aspects, the light sensor is a smartphone used to detect lighttransmitted through the asymmetric microlens array.

In some aspects, the light sensor is an optical power meter used todetect light reflected from the asymmetric microlens array.

In some aspects, the asymmetric microlens array has at least one of thefollowing characteristics: microlenses having at least one of thefollowing surfaces: a convex aspherical surface, a plano-convexaspherical surface, a convex-concave aspherical surface, a convexspherical surface, a plano-convex spherical surface, and aconvex-concave spherical surface; microlenses which are non-uniformlyspaced apart; microlenses which are arranged in a non-periodicconfiguration; microlenses which are arranged in a non-orderedconfiguration; at least two microlenses having different surfacetopologies; at least two microlenses having different base geometries;and at least two microlenses having different heights.

The following Examples are intended to illustrate the above inventionand should not be construed as to narrow its scope. One skilled in theart will readily recognize that the Examiners suggest many other ways inwhich the invention could be practiced. It should be understood thatnumerous variations and modifications may be made while remaining withinthe scope of the invention.

Example 1 Hydrogel Alcohol Sensor Fabrication

Ethylene glycol dimethacrylate (EGDMA) (98%), 2-hydroxyethylmethacrylate (HEMA) (97%), 2,2-dimethoxy-2-phenylacetophenone (DMPA)(99%), polyethylene glycol diacrylate (PEGDA) (mw: 700 Da),2-hydroxy-2-methylpropiophenone (2-HMP) (97%), dimethyl sulfoxide (DMSO)(99.9%), ethanol, propan-2-ol, sodium phosphate monobasic (NaH₂PO₄),sodium phosphate dibasic (NaH₂PO₄), and acrylic acid (AA) were purchasedfrom Sigma Aldrich and used without further purification.

The precursor consisted of HEMA (92.5 mol %) and EGDMA (7.5 mol %) wasmixed with DMPA (2% wt/vol) in propan-2-ol. The monomer solution (20 μl)was drop cast on the asymmetric microlens arrays (diffuser surface),covered with a salinized glass piece, and cured by a UV lamp (365 nm)for 1 h. The polymerized sensor was washed with DI water/ethanol (1:1,v/v) and preserved at 24° C.

Example 2 Hydrogel pH Sensor Fabrication

Ethylene glycol dimethacrylate (EGDMA) (98%), 2-hydroxyethylmethacrylate (HEMA) (97%), 2,2-dimethoxy-2-phenylacetophenone (DMPA)(99%), polyethylene glycol diacrylate (PEGDA) (mw: 700 Da),2-hdroxy-2-methylpropiophenone (2-HMP) (97%), dimethyl sulfoxide (DMSO)(99.9%), ethanol, propan-2-ol, sodium phosphate monobasic (NaH₂PO₄),sodium phosphate dibasic (NaH₂PO₄), and acrylic acid (AA) were purchasedfrom Sigma Aldrich and used without further purification.

The precursor consisted of HEMA (91.5 mol %), EGDMA (2.5 mol %), andacrylic acid (6 mol %), was mixed with DMPA in propan-2-ol (2%, wt/vol).The monomer solution (20 μl) was pipetted on the asymmetric microlensarrays, covered with a salinized glass piece, and cured by the UV lamp(365 nm) for 1 h. The polymerized sensor was washed with DIwater/ethanol (1:1, v/v) and preserved at 24° C.

Example 3 Hydrogel Optical Fiber Fabrication

PEGDA monomer was mixed with 2-hydroxy-2-methylpropiophenone (2-HMP) (5vol %) in DI water. The dilution of PEGDA in DI water was varied from 5to 90 vol %. The prepared solution (200 μl) was injected into apolyvinyl chloride tube having an inner diameter of 1 mm and the tubewas exposed to UV light (365 nm) for 30 min. The optical fiber wasextracted from the tube by applying water pressure using a syringe. Theoptical fiber was washed with a mixture of ethanol and DI water (1:1,v/v). The tip of the fiber was functionalized with the pH-sensitivehydrogel by dipping the tip in a pH-sensitive solution (10 μl) that waspipetted on the asymmetric microlens arrays and was exposed to UV lightfor 1 h. To create a probe, the tip of the fiber was salinized anddipped in either alcohol or pH-sensitive solutions during the curingprocess. The functionalized tip was washed in DI water/ethanol (1:1,v/v) and preserved at 24° C.

Example 4 Testing the Hydrogel Sensor Constrained on the Glass Slide

The stimuli-responsive hydrogel imprinted with microlens arrays andattached chemically on the glass slide was submerged in 1 ml of thetested solution in a plastic cuvette fixed on a rotating stage. Whitelight source or laser pointer was fixed on the same rotating stage toilluminate the senor. S_(t), and P_(t) were recorded by a photodiodethat was fixed and immobile on the optical bench. Also, the smartphonewas fixed to pick up the maximum transmitted luminance (L_(t))exploiting the ambient light senor of smartphone for sensingmeasurements.

Example 5 Testing the Fiber Probe in the Transmission Mode

The fiber probe was coupled with a white light source/laser pointer atone end and the other end that is functionalized was soaked in thetested solution container. Below the tested solution container, thephotodiode detector/smartphone was fixed to collect the P_(t)/L_(t).

Example 6 Testing the Fiber Probe in the Reflection Mode

The fiber probe was coupled with the seven fibers terminal of 2×1coupler. The light source was connected with the coupler terminal ofonly one fiber and the photodiode was connected with coupler terminal ofsix fibers. Therefore, one fiber was illuminating the sensing probe andthe six fiber were collecting the reflected light in the probe to beguided into the photodetector.

Example 7 Glucose Monitoring

Materials. Polyethylene glycol diacrylate (PEGDA) (mw: 700 Da),acrylamide (AM) (98%), 3-(acrylamido)-phenylboronic acid (3-APBA) (98%),sodium L-lactate, N,N-methylenebisacrylamide (99%), D-(+) glucose(99.5%), 2,2-dimethoxy-2-phenylacetophenone (DMPA) (99%),2-hdroxy-2-methylpropiophenone (2-HMP) (97%), phosphate buffered salinetablets (PBS), dimethyl sulfoxide (DMSO) (99.9%), sodium phosphatemonobasic (NaH₂PO₄), and sodium phosphate dibasic (NaH₂PO₄) werepurchased from Sigma Aldrich and used without further purification.

Example 8 Fabrication of the Hydrogel Sensor Constrained on a GlassSlide

The precursor solution consisted of acrylamide (78.5 mol %), N,N′-methylenebisacrylamide (1.5 mol %), and 3-APBA (20 mol %) was mixedwith DMPA (2% wt/vol) in DMSO and the monomer dilution was 1:2 wt/vol.The monomer solution (100 μl) was drop-cast on the asymmetric microlensarray surface, and subsequently, was covered with a salinized glasspiece, and was polymerized by UV lamp (365 nm) for 5 min. Thepolymerized sensor was washed with DI water/ethanol (1:1 v/v) andpreserved in PBS solution at pH 7.4.

Example 9 Functionalization of the Silica and the Hydrogel Fibers

To functionalize the optical fiber with the glucose responsive hydrogel,the fiber's tip was silanized and dipped in the glucose-sensitivesolution (10 μl) that was drop-cast on the asymmetric microlens arraysurface (AMLA) and was exposed to the UV light for 5 min. Thefunctionalized fiber was preserved in the PBS solution at pH 7.4.

Example 10 Fabrication of the Biocompatible Optical Fiber

PEGDA monomer was mixed with 2-hydroxy-2-methylpropiophenone (2-HMP) (5vol %) in DI water. The dilution of PEGDA in DI water was varied from 5to 90 vol %. The prepared solution (200 μl) was injected into apolyvinyl chloride tube with an inner diameter of 1 mm and the tube wasexposed to UV light (365 nm) for 30 min. The optical fiber was extractedfrom the tube by applying water pressure using a syringe. The opticalfiber was washed with a mixture of ethanol and DI water (1:1, v/v).

What is claimed is:
 1. A fiber optic probe comprising: an optical fiber,and a sensor component attached to the optical fiber, the sensorcomponent including light diffusing microstructures imprinted on astimuli-responsive hydrogel, wherein the light diffusing microstructuresform an asymmetric microlens array.
 2. The fiber optic probe of claim 1,wherein the optical fiber is a biocompatible hydrogel fiber.
 3. Thefiber optic probe of claim 1, wherein the asymmetric microlens arrayincludes one or more microlenses, each of the one or more microlensesindependently having a convex aspherical surface, a plano-convexaspherical surface, a convex-concave aspherical surface, a convexspherical surface, a plano-convex spherical surface, or a convex-concavespherical surface.
 4. The fiber optic probe of claim 1, wherein theasymmetric microlens array has at least one of the followingcharacteristics: microlenses which are non-uniformly spaced apart;microlenses which are arranged in a non-periodic configuration;microlenses which are arranged in a non-ordered configuration; at leasttwo microlenses having different surface topologies; at least twomicrolenses having different base geometries; and at least twomicrolenses having different heights.
 5. A fiber optic probe of claim 1,wherein the sensor component includes a glucose-responsive hydrogel. 6.The fiber optic probe of claim 5, wherein the glucose-responsivehydrogel sensor includes acrylamide; N,N′-methylenebisacrylamide;3-(acrylamido)-phenylboronic acid (3-APBA); and2,2-dimethoxy-2-2phenylacetophenone (DMPA).
 7. A fiber optic probe ofclaim 1, wherein the sensor component includes an alcohol-responsivehydrogel.
 8. The fiber optic probe of claim 7, wherein thealcohol-responsive hydrogel sensor includes 2-hydroxyethylmethacrylate(HEMA); ethylene glycol dimethacrylate (EGDMA); and2,2-dimethoxy-2-phenylacetophenone (DMPA).
 9. A fiber optic probe ofclaim 1, wherein the sensor component includes a pH-responsive hydrogel.10. The fiber optic probe of claim 9, wherein the pH-responsive hydrogelsensor includes 2-hydroxyethylmethacrylate (HEMA); ethylene glycoldimethacrylate (EGDMA); acrylic acid (AA); and2,2-dimethoxy-2-phenylacetophenone (DMPA).
 11. A method of fabricating afiber optic probe, comprising: (a) depositing a light-curablestimuli-responsive hydrogel precursor solution on a substrate moldhaving a surface including an inverse asymmetric microlens array; (b)contacting an end portion of an optical fiber with the light-curablestimuli-responsive hydrogel precursor solution deposited on thesubstrate mold; and (c) exposing the end portion of the optical fiberand light-curable stimuli-responsive hydrogel precursor solution tolight to form a stimuli-responsive hydrogel sensor imprinted with anasymmetric microlens array and attached to the end portion of theoptical fiber.
 12. The method of claim 11, wherein the light-curablestimuli-responsive hydrogel is synthesized, imprinted with theasymmetric microlens array, and attached to the end portion of theoptical fiber in step (c).
 13. The method of claim 11, wherein thelight-curable stimuli-responsive hydrogel precursor solution includes atleast the following: a monomer, a crosslinking agent, and aphotoinitiator.
 14. The method of claim 11, wherein the substrate moldis fabricated by: depositing a light-curable prepolymer solution on amaster light diffuser having a surface including a master asymmetricmicrolens array; exposing the deposited light-curable prepolymersolution to light to cure the prepolymer; and releasing the curedprepolymer from the master light diffuser to obtain the substrate mold,the substrate mold including the inverse asymmetric microlens array. 15.The method of claim 11, wherein the optical fiber is fabricated by:injecting a light-curable monomer solution into a tubular body; exposingthe monomer solution to light to initiate polymerization; and extractinga polymerized fiber from the tubular body to obtain the optical fiber.16. The method of claim 11, wherein the asymmetric microlens arrayincludes one or more microlenses, each of the one or more microlensesindependently having a convex aspherical surface, a plano-convexaspherical surface, a convex-concave aspherical surface, a convexspherical surface, a plano-convex spherical surface, or a convex-concavespherical surface.
 17. A system comprising: a fiber optic probeincluding an optical fiber and a sensor component attached to theoptical fiber, the sensor component including an asymmetric microlensarray imprinted on a stimuli-responsive hydrogel; a light source coupledto the fiber optic probe, wherein the light source is configured totransmit light through the optical sensor; and a light sensor fordetecting light transmitted through the asymmetric microlens array orlight reflected from the asymmetric microlens array.
 18. The system ofclaim 17, wherein the light sensor is a smartphone used to detect lighttransmitted through the asymmetric microlens array.
 19. The system ofclaim 17, wherein the light sensor is an optical power meter used todetect light reflected from the asymmetric microlens array.
 20. Thesystem of claim 17, wherein the asymmetric microlens array has at leastone of the following characteristics: microlenses having at least one ofthe following surfaces: a convex aspherical surface, a plano-convexaspherical surface, a convex-concave aspherical surface, a convexspherical surface, a plano-convex spherical surface, and aconvex-concave spherical surface; microlenses which are non-uniformlyspaced apart; microlenses which are arranged in a non-periodicconfiguration; microlenses which are arranged in a non-orderedconfiguration; at least two microlenses having different surfacetopologies; at least two microlenses having different base geometries;and at least two microlenses having different heights.